3.5.1. Achyranthes Aspera

Achyranthes aspera is a plant used as an anti-cancer agent in traditional medicine in India. Chemical investigation of the seeds of this plant resulted in isolation and identification of saponin A (as D-glucuronic acid) and saponin B (as β-D-galactopyranosyl ester of D-glucuronic acid). Certain other constituents were also isolated, including oleanolic acid, amino acids, and hentriacontane. The seeds also contain 10-tricosanone, 10-octacosanone, and 4-tritriacontanone [178]. The plant has been shown to exhibit time- and dose-dependent cytotoxicity on PC cells. It also selectively suppresses the transcription of metalloproteases, inhibitors of MMPs, and angiogenic factors [89].

3.5.2. Alpinia officinarum

Alpinia officinarum is a plant in the ginger family, cultivated in Southeast Asia. The rhizomes of the plant have been used in curries and perfumes. It contains high amounts of the flavonol galangin. Dong et al. showed that these diarylheptanoids contained in Alpinia officinarum suppressed cell proliferation, and induced the cell cycle arrest of PC cells [90].

3.5.3. Amoora rohituka

Amoora rohituka is a plant found in many districts of Bangladesh. The species of the plant contain several triterpenoids, including limonoids, steroids, an alkaloid, a chromone (noreugenin), three flavonoid glycosides, and straight-chain aliphatic compounds [179]. The extracts of this plant have been studied for their anti-inflammatory, antibacterial, and anticancer properties. Rabi et al. found that Aphanin, one of the isolated novel triterpenoid compounds, exhibited antiproliferative effects, caused G₀-G₁ cell cycle arrest, inhibited K-Ras G12D mutant activity, and induced apoptosis in PC HPAF-II cells [91].

3.5.4. (Ancistrocladaceae) liana

Ancistrocladaceae is the name of flowering plants growing in the tropics. The active ingredient is michellamine B, an isoquinoline alkaloid that can be found in the mature leaves. A number of other alkaloids have also been isolated that display strong cytotoxic activities against PC cell lines in nutrient-deprived media, without toxicity in normal, nutrient-rich conditions [180]. Li et al., using two newly discovered naphthylisoquinoline dimers, along with the known dimer jozimine A₂, showed that they have strong cytotoxic activities against human PC cells under nutrition-deprived conditions [92].

3.5.5. Apigenin

Apigenin (4′,5,7-trihydroxyflavone), a natural product found in many fruits and vegetables, mainly in the flowers of chamomile plants, belongs to the flavone class. Johnson et al. investigated the inhibitory effects of the citrus fruit bioactive compounds, namely flavonoids, limonoids, phenolic acids, and ascorbic acid, on human PC cells. Apigenin showed strong anticancer activity through the induction of pancreatic cell death arrest of the cell cycle at the G2 /M phase, and activation of the mitochondrial pathway of apoptosis. Apigenin could also up-regulate the expression of a number of cytokine genes in BxPC-3 cells [93]. Moreover, apigenin has been shown to sensitize PC cells to chemotherapy by affecting a number of molecular pathways [94].

3.5.6. Asteraceae and Lamiaceae

The Lamiaceae or Labiatae is a family of aromatic flowering plants that includes herbs such as basil, mentha, rosemary, sage, savory, marjoram, oregano, thyme, and lavender. These plants contain phenolic compounds, especially flavonoids [181]. The effects of different Asteraceae (Achillea millefolium and Calendula officinalis) and Lamiaceae (Melissa officinalis and Origanum majorana) plant extracts against human PC cells were tested. In an experimental study, Asteraceae extracts showed significant antitumor activity by inducing cytotoxicity, and inhibiting cell transformation [95].

3.5.7. Bitter Melon Juice

Bitter melon juice contains a large number of phytochemicals, flavonoids, triterpenes, saponins, ascorbic acid, steroids, proteins, and polysaccharides. Kaur et al. showed that bitter melon juice decreased the viability of PC cell lines by inducing apoptotic death. At the molecular level, it caused caspase activation, altered Bcl-2 expression, and decreased 22-signaling and X-linked inhibitor of apoptosis protein levels. The oral administration of bitter melon juice in mice inhibited MiaPaCa-2 tumor xenograft growth by 60% without side-effects [96].

3.5.8. BRM270

BRM270 is a natural compound used in Asian traditional medicine, made from seven herbal plant extracts (Saururus chinensis, Citrus unshiu Markovich, Aloe vera, Arnebia euchroma, Portulaca oleracea, Prunella vulgaris var. lilacina, and Scutellaria bacicalensis). BRM270 is considered to be the most important phytochemical extract that possesses anticancer properties, although its low bioavailability makes the administration of high dosages necessary in order to obtain positive results. Huynh et al. investigated the effect of BRM270 on the isolated surface market CD44 positive PC cells. They showed that BRM270 induced apoptosis in these cells, and inhibited metastasis traits via the sonic hedgehog signaling pathway. Moreover, in an in vivo experiment, tumor growth derived from CD44⁺ PDAC was suppressed [97]. It seems that the administration of this phytochemical extract selectively targeting CD44⁺ PDAC cells in tumors might be an effective approach against pancreatic tumorigenesis. BRM270 also has the advantage of being effective in PC cells resistant to paclitaxel and gefitinib [98].

3.5.9. Boesenbergia pandurata

Boesenbergia rotunda is a medicinal herb growing mainly in China and Southeast Asia. Nearly a hundred compounds were isolated and elucidated, includung flavonoid and chalcone derivatives, esters, kawains, terpenes, and terpenoids. It is specifically used as a spice, or as a flavoring agent, or in traditional medicine in patients with liver cirrhosis. Its rhizomes have been used in various disorders, including oral eczema, ulcers, and dry mouth. Its extracts improve candidiasis, especially in patients with HIV infection, dysentery, and abdominal pain. A recently described observation, according to which human PC cell lines exhibit a significant tolerance to nutrition starvation agents that could inhibit the survival of cancer cells under low nutrient conditions, might be a very interesting novel strategy in the treatment of PC. In this regard, Nguyen et al. tested an extract of the rhizomes of Boesenbergia pandurata against human PC cells under nutrient-deprived conditions. They showed that the isolates isopanduratin A1 and nicolaioidesin C exhibited the strongest cytotoxicity against human PC cells under nutrition-deprived conditions [99].

3.5.10. Boswellia sacra Gum Resins

Gum resins from Boswellia species have been used in Ayurvedic and Chinese medicine in a number of clinical applications, including for malignant disorders. Ni et al. showed that crude essential oil prepared from hydrodistillation of Boswellia sacra gum resins could reduce viability, and increase cancer cell death. Human PC cells showed reduced viability, and increased death after treatment with fractions III and IV. Boswellia sacra essential oil Fraction IV also exhibited anticancer activities against PC in the heterotopic xenograft mouse model [100]. Although the responsible chemical compounds were not identified, Boswellia sacra gum resins are promising agents for the treatment of PC.

3.5.11. Bruceine D

Brucea javanica is a shrub belonging to the family Simaroubaceae, growing naturally in a number of countries, including Sri Lanka and India to China, Malesia, New Guinea, and Australia. The fruit Brucea javanica contains quassinoid compounds that have anticancer and antiparasitic properties. Brucea javanica oil emulsion has been employed as adjunctive therapy for the treatment of various cancers. The mechanisms of antitumor activity may include inhibition of DNA polymerase activity, arrest of the tumor cell division cycle, disruption of the cellular energy metabolism, and depression of the expression of vascular endothelial growth factor. Liu et al. showed that bruceine D has a potent cytotoxic effect on PC cell lines. Bruceine D induces cytotoxicity in Capan-2 cells via the induction of cellular apoptosis involving the mitochondrial pathway. The antiproliferative effects of bruceine D were comparable to those exhibited by camptothecin and gemcitabine. Finally, the expression of both caspase 9 and caspase 3 in BD-treated Capan-2 cells was accentuated [101]. Brucea javanica oil emulsion can effectively reverse the multidrug resistance of tumor cells, thus increasing the sensitivity of cancer cells to chemotherapy and radiotherapy. Yang et al. found that the combination of Brucea javanica with gemcitabine in a PC patient-derived orthotopic xenograft mouse model resulted in a reduced tumor growth rate, and increased apoptosis compared to the vehicle control and gemcitabine alone, as well as increased survival. Taken together, all of these results unequivocally indicate that this plant has a therapeutic potential for PC [102].

3.5.12. Cannabinoids

Cannabinoids are chemicals found in cannabis. Phytocannabinoid tetrahydrocannabinol represents the primary psychoactive compound of cannabis. There are at least 113 different cannabinoids isolated from cannabis, exhibiting varied therapeutic effects, including improvement of the outcome of cancer patients. In vitro studies have shown that cannabidiol has antiproliferative and proapoptotic effects mediated through cannabinoid receptor-1 and -2, and G-protein-coupled receptor 55 pathways. In vitro studies with cannabidiol, tetrahydrocannabinol, and synthetic derivatives also demonstrated tumor growth-inhibiting effects. The combination of cannabidiol cannabidiol/synthetic cannabinoid receptor ligands and chemotherapy in xenografts showed positive results [103].

3.5.13. Citrus Unshiu Peel

Citrus Unshiu, 1 of the more than 900 citrus species known today, is a seedless, easy to peel tangerine, coming from the Japanese town, Satsuma. The chemical constituents of the citrus unshiu flower include γ-terpinene (24.7%), 2-β-pinene (16.6%), 1-methyl-2-isopropylbenzene (11.5%), L-limonene (5.7%), β-ocimene (5.6%), and α-pinene (4.7%) [182]. Lee et al. prepared a fermented extract of Citrus unshiu peel from the byproduct after juice processing, and examined its anticancer effects on PC cells. They found that fermented Citrus unshiu peel mainly consists of aboriginal compounds (narirutin and hesperidin), as well as newly generated compounds (naringenin and hesperetin). Treatment with fermented Citrus unshiu peel inhibited the growth of human PC cells through the induction of caspase-3 cleavage both in vitro and in vivo. Moreover, Citrus unshiu peel also blocked the migration of the PC cells through the activation of intracellular signaling pathways [104]. Naringenin and hesperetin were the unique modules related to its anticancer effect. In in vivo xenograft models, fermented Citrus unshiu peel also showed anticancer effects, suggesting that this product might be an effective anticancer drug for PC with no side-effects.

3.5.14. Cloves (Syzygium aromaticum)

Cloves are the aromatic flower buds of a tree in the family Myrtaceae, Syzygium aromaticum. They are native in Indonesia, used as a spice. Clove oil containing eugenol could be effective in pain of various origins, although no supporting data exist. Again, inconclusive results were obtained from studies investigating its efficacy in fever and diabetes. Therefore, the use of cloves for any medicinal purpose has not been approved by the FDA of the USA. Some side-effects have also been described in patients suffering from liver, and blood clotting and immune system disorders. However, in the study of Li et al., the aqueous extract of cloves inhibited cancer cell growth, and diminished the colony formation on several cancer cell lines, including human PC cells. An in vivo study revealed that aqueous extract of cloves inhibited the tumor growth in a HT-29 xenograft mice model by inducing cell autophagy [105].

3.5.15. Cocoa Polyphenol

Epicatechin is the major polyphenol contained in cocoa. Siddique et al. showed that treatment with cocoa polyphenol and epicatechin decreased the NF-κB transcriptional activity of premalignant and malignant Kras-activated pancreatic ductal epithelial cells, concurrently decreasing their proliferation, the guanosine triphosphate-bound Ras protein, and the Akt phosphorylation [106]. Furthermore, the oral administration of 25 mg/kg of cocoa polyphenol inhibited the growth of Kras-PDE cell-originated tumors in a xenograft mouse model.

3.5.16. Cordyceps Militaris

Cordyceps militaris is a species of fungus in the family Cordycipitaceae. It represents an entomopathogenic fungus, which is widely used in traditional Chinese medicine as a general booster for the nervous system, metabolism, and immunity. A variety of substances, including saccharides, nucleosides, mannitol, and sterols, have been isolated from this fungus. The biological activity of Condyceps militaris is attributed to the saccharide and nucleoside contents. In a recently published study, Li et al. demonstrated that Cordycepin inhibits PC growth in vitro and in vivo via targeting FGFR2, and blocking ERK signaling [107].

3.5.17. Crocus Sativus

Crocin, the main component of Crocus sativus, is one of the few water soluble carotenoids found in nature [183]. In an experimental study, it was shown that Crocin induced apoptosis and cell cycle arrest of BxPC-3 human PC cell lines, and decreased cell viability. The mechanism of action seems to be related with the induction of apoptosis of the malignant cells [108].

3.5.18. Cryptotanshinone

Salvia miltiorrhiza is a perennial plant of the genus Salvia. The chemical compositions of this herb are hydrophilic phenolic compounds and lipid-soluble diterpenoid compounds that are responsible for its pharmacological activities. The tanshinones in Salvia miltiorrhiza are diterpenoid quinones, which can be classified into two series, one is the phenanthro [1,2-b] furan-10,11-diones; and the other is the phenanthrol [3,2-b] furan-7, 11-diones. Alone or combined with other herbal medicines, Salvia miltiorrhiza has been used in China as a treatment for cardiovascular and cerebrovascular diseases, although a number of meta-analyses suggest that the effects of the plant are inconclusive. Adverse effects may include allergic reactions, dizziness, headache, gastrointestinal complaints, and bleeding in patients taking warfarin. Danshen may have anti-hypertensive and anti-platelet aggregation effects, and may enhance endogenous anti-oxidative enzyme activities. Cryptotanshinone, one of the active constituents of Salvia miltiorrhiza, has been shown to exhibit significant antitumor effects in several cancer cells [109]. Ge et al. demonstrated that cryptotanshinone inhibited proliferation, and induced cell apoptosis and cell cycle arrest in PC cells. In addition, cryptotanshinone decreased the activities of signal transducer, as well as several upstream regulatory signaling pathways [110].

3.5.19. Cucurbitacin E

Cucurbitacin E belongs to a triterpenoid family, isolated from plants, and shows antiproliferative activity on various cancer cells. Cucurbitacin E inhibited the growth of PANC-1 cells and apoptosis, inhibited STAT3 phosphorylation, and up-regulated p53 expression [111].

3.5.20. Cucurmosin

The structure of Cucurmosin has been proved to be one of the type 1 ribosome-inactivating proteins. Xie et al. established an NOD-SCID mice orthotopic transplantation model, and estimated the proliferation inhibition effect of Cucurmosin in SW-1990 cells in vivo. Cucurmosin inhibited the proliferation of PC cells, and induced apoptosis in a dose- and time-dependent manner. In the NOD-SCID mice models, the tumor proliferation inhibition rates were increased compared with controls. Cucurmosin inhibited the examined proteins in the PI3K/Akt/mTOR signaling pathway, and induced active fragments of Caspase 3 and 9 [112]. Cucurmosin can inhibit the growth and induce apoptosis of the human PC cell line SW-1990 both in vitro and in vivo.

3.5.21. Dandelion root Extract

Dandelion root has been used in traditional Chinese and Native American medicine in various liver and gastric disorders. The therapeutic properties of Dandelion are attributed to its bioactive chemical components, including chicoric acid, taraxasterol, chlorogenic acid, and sesquiterpene lactones [184]. In an experimental study, Dandelion root extract induced selective apoptosis, as well as collapse of the mitochondrial membrane potential, leading to prodeath autophagy [113].

3.5.22. Degalactotigonin

Solanum nigrum is a species in the genus Solanum, native to Eurasia, and introduced in America, Australasia, and South Africa. Solanum nigrum is a widely used plant in oriental medicine, considered to have anticancer, antioxidant, anti-inflammatory, hepatoprotective, diuretic, and antipyretic properties. However, ripe berries can cause symptoms such as fever, sweating, vomiting, abdominal pain, diarrhea, confusion, and drowsiness. Death after ingesting large amounts of the plant has been observed. Degalactotigonin solasodine a steroidal glycoside isolated from Solanum nigrum which showed cytotoxicity, and induced apoptosis in PC cell lines. It also inhibited EGF-induced proliferation and migration, and induced down-regulation of cyclin D1. Furthemore, it inhibited EGF-induced phosphorylation of EGFR, as well as activation of EGFR downstream signaling molecules [114].

3.5.23. Diterpene 25 Signaling

Pyruvate dehydrogenase kinase 4 expression is up-regulated in various cancer tissues, being a suitable target for cancer therapy given its ability to shift glucose metabolism. Tambe et al. identified natural diterpene 25 signaling (KIS compounds) that inhibits pyruvate dehydrogenase kinase 4. They showed that KIS37 (cryptotanshinone) inhibited KRAS-activated human PC cell lines, and suppressed KRAS protein expression. Furthermore, KIS37 suppressed phosphorylation of Rb and cyclin D1 proteins, as well as the expression of cancer stem cell markers. KIS37 also suppressed PC cell growth in both subcutaneous xenograft and orthotopic pancreatic tumor models [115]. Therefore, KIS37 should be considered as a novel therapeutic strategy for targeting PDK4 in KRAS-activated PC.

3.5.24. Elemene

Elemenes are a group of chemical compounds found in a variety of plants. Chemically, they are structural isomers of each other, and are classified as sesquiterpenes. They could be found in a variety of medical plants. Bearing in mind the antiproliferative effects of this compound, Long et al. investigated different doses of elemene in mice undergoing subcutaneous xenograft with BxPC-3 PC cells. In the in vitro experiment, a significant antiproliferative effect of BxPC-3 and Panc-1 cells was observed. In the in vivo BxPC-3 xenografts, elemene decreased the tumor size, up-regulated the expression of P53, and down-regulated the expression of Bcl-2 in the tumor [116]. The mechanisms of action against PC are related to down-regulation of the expression of Bcl-2, and up-regulation of the expression of P53.

3.5.25. Ellagic acid

Ellagic acid is a natural polyphenol antioxidant found in a number of plants and fruits. This chemical substance is considered to be a dietary supplement with antineoplastic characteristics. However, Ellagic acid has been characterized by the USA FDA as a “fake cancer cure’”. It has been suggested that urolithin A, microflora metabolites of dietary ellagic acid derivatives, might have anticancer effects. Zhao et al. showed that treatment of PANC-1 xenografted mice with Ellagic acid resulted in a significant inhibition in tumor growth; suppression of cell proliferation and caspase-3 activation; induction of PARP cleavage; inhibition of the expression of Bcl-2, cyclin D1, CDK2, and CDK6; and induction of the expression of Bax in tumor tissues. Other effects included the inhibition of angiogenesis and metastasis in tumor tissues [117]. In a more recent study, Cheng et al. found that Ellagic acid significantly inhibited human PC PANC-1 cell growth, cell repairing activity, and cell migration and invasion. On the other hand, treatment of PANC-1 xenografted mice with Ellagic acid resulted in a significant inhibition in tumor growth, and prolongation of the mice survival rate. [118]. The use of Ellagic acid would be beneficial for the management of PC.

3.5.26. Emodin

Emodin (1, 3, 8-trihydroxy-6-methylanthraquinone), a Chinese medicinal herb with antineoplastic action, represents the active constituent isolated from the root of Rheum palmatum L. In a study aiming to investigate its antineoplastic action, Liu et al. noticed that emodin induced significant growth inhibition and apoptosis in the PC cell line SW1990 compared to that of control, concurrently suppressing the migration and invasion of SW1990 cells. Emodin down-regulated the NF-κB DNA-binding activity in SW1990 cells, and up-regulated the expression of caspase-3. In addition, the oral administration of emodin decreased tumor weight and metastasis [119].

3.5.27. Eryngium billardieri

Eryngium represents a genus of flowering plants belonging to the family Apiaceae, with a global distribution. Eryngium contains several chemical constituents, including sesquiterpenes and monoterpenes as the main components, as well as aldehydes, coumarins, sitosterols, and sugars. They are annual and perennial herbs with spiny leaves. Some species are native to rocky and coastal areas, but the majority of them are grassland plants. Many species of Eryngium have been used in food and medicine against diabetes mellitus, and as an antiinflammatory agent [120]. Roshanravan et al. have shown that Eryngium billardieri extracts had cytotoxic effects on PANC-1 cancer cell lines, and induced apoptosis [121]. Moreover, treatment of cancer cells with dichloromethane and n-hexane extracts of Eryngium billardieri induced the overexpression of Bax and underexpression of cyclin D1.

3.5.28. Eucalyptus

Eucalyptus is a genus of over seven hundred species of flowering trees, shrubs, or mallees in the myrtle family commonly known as eucalypts. Although eucalyptus mainly grows in Australia, other species are now distributed globally. Being a natural insecticide, it can indirectly reduce the risk of malaria. Eucalyptus oils have been used in the pharmaceutical and cosmetics industries for multiple purposes. It has been used for the treatment of flu, fever, muscular aches, sores, pains of various origin, and inflammation. Eucalypts have been linked with cytotoxic and anticancer properties, although little scientific evidence exists [122]. Bhuyan et al. assessed the anticancer properties of aqueous and ethanolic extracts of four Eucalyptus species, and found these exctracts inhibited the growth of PC cells by more than 80% at 100μg/mL. Caspase 3/7-mediated apoptosis and morphological changes of cells were also witnessed in MIA PaCa-2 cells [123]. In a subsequent study [124], the same group of investigators found that Angophora floribunda extract exerted a greater cell growth inhibition followed by A. hispida in MIA PC-2 cells.

3.5.29. Ferula Hezarlalehzarica

The genus Ferula comprises more than 170 species worldwide, of which 30 grow in Iran. These plants have been used traditionally for treating skin infections and stomach disorders. So far, there is a lack of phytochemical investigations of this plant. Alilou et al. isolated and evaluated 18 compounds, and found that the dichloromethane extract of the roots of Ferula hezarlalehzarica is a rich source of bioactive compounds for targeting PANC-1 cells [125].

3.5.30. Gallic acid

In a relevant study, a grape seed procyanidin extract significantly inhibited cell proliferation, and increased apoptosis in PC cells through down-regulation of the antiapoptotic protein Bcl-2, depolarization of the mitochondrial membrane, and reduction of the formation of reactive oxygen species. Gallic acid had the highest antiproliferative and proapoptotic activity [126].

3.5.31. Garlic

Garlic (Allium sativum) represents a species in the onion genus, Allium. An inverse association between garlic intake and gastric cancer was previously suggested. A number of side-effects, including gastrointestinal discomfort, sweating, dizziness, allergic reactions, bleeding, menstrual irregularities, and bad breath (halitosis), have been described. Wang et al. investigated a novel garlic active component (S-propargyl-L-cysteine), and showed that this substance reduced cell viability and colony formation, inhibited cell proliferation, and induced G2/M phase cell cycle arrest and apoptosis in human PC cells. It also inhibited tumor growth in Panc-1 xenografts by regulating the JNK protein levels [127]. Lan et al. [128] observed morphologic changes of PC cells under transmission electron microscopy after treatment with garlic oil for 24 h. In the higher garlic oil concentrations, an earlier change of the apoptotic tendency was detected.

3.5.32. Gedunin (Azadirachta indica)

Gedunin is a tetranortriterpenoid isolated from the Indian neem tree Azadirachta indica. It has been used for the treatment of malaria and other infectious diseases in traditional Indian medicine. In addition, gedunin has demonstrated antiproliferative activity against various cancer cell lines. Subramani et al. assessed the anti-metastatic potential of gedunin on PC cells using matrigel invasion, cratch, and soft agar colony formation assays. They found that gedunin treatment was highly effective in inducing the apoptosis of PC cells. Furthermore, gedunin inhibited metastasis of PC cells by decreasing their invasive, migratory, and colony formation capabilities [129].

3.5.33. Ginger Extract

Ginger is a plant native to warmer parts of Asia, but now is growing also in parts of South American and Africa. It is likely safe when taken appropriately, although it can cause mild side-effects, including heartburn, diarrhea, abdominal discomfort, and extra menstrual bleeding. Ginger spice comes from the roots of the plant. The extract of ginger and its major pungent components have an anti-proliferative effect on several tumor cell lines. Akimoto et al. demonstrated that the ginger ethanol-extracts suppressed cell cycle progression, and increased the death of human PC cell lines by inducing autosis, a form of cell death. Daily intraperitoneal administration of the extract prolonged survival in a peritoneal dissemination model, and suppressed tumor growth in an orthotopic model of PC [130].

3.5.34. Ginkgolic Acid

Ginkgolic acid is a botanical drug extracted from the seed coat of Ginkgo biloba L., harboring anti-tumor effects. It has been used for centures in China and in Europe (Germany) some decades ago, in the treatment of Alzheimer’s disease. However, Ginkgo biloba leaf extracts may have undesirable effects in patients taking anticoagulants. Other side-effects include nausea, vomiting, diarrhea, headache, dizziness, and heart palpitations. It should be avoided during lactation. Ma et al. showed that Ginkgo biloba leaf extracts reduced the viability of cancer cells without toxic effects on normal cells. Ginkgo biloba leaf extracts also impaired colony formation, migration, and invasion ability, and increased apoptosis of cancer cells through the activation of AMP-activated protein kinase signaling and down-regulation of the expression of key enzymes involved in lipogenesis [131].

3.5.35. Grape Proanthocyanidin

It has been found that in vitro treatment of human PC cells with proanthocyanidins from grape seeds resulted in a significant reduction in the cell viability, as well as a significant increase of G2/M phase arrest, induction of apoptosis, decrease in the levels of Bcl-2 and Bcl-xl, and increase in the levels of Bax and activated caspase-3. On the other hand, in vivo experiments using diet supplementation with proanthocyanidins from grape seeds on Miapaca-2 pancreatic tumor xenografts grown subcutaneously in athymic nude mice resulted in reduction of tumor growth, increased expression of Bax, reduction of anti-apoptotic proteins, and activation of caspase-3-positive cells [132].

3.5.36. Graviola

The tropical tree Annona Muricata, commonly known as graviola, has been shown to have some anticancer properties. More than 200 chemical compounds have been identified and isolated from this plant; the most important being alkaloids, phenols, and acetogenins [185]. Torres et al. showed that graviola extract induced necrosis of PC cells by inhibiting cellular metabolism, and down-regulating the expression of NFκB [133]. In vitro functional assays confirmed the inhibition of growth of PC cells, suggesting that graviola extract is able to inhibit multiple signaling pathways regulating metabolism, survival, and metastatic potential of PC cells.

3.5.37. Green Tea Extract

Green tea polyphenols have been shown to exhibit multiple antitumor activities in various cancers. Zhang et al. showed that green tea extract inhibited molecular chaperones heat-shock protein 90, its mitochondrial localized homologue Hsp75, and heat-shock protein 27, concomitantly. Furthermore, green tea extract inhibited Akt activation and the levels of mutant p53 protein, and induced apoptosis and growth suppression of the cells. The authors of this study discovered new molecular targets of the green tea extract, and provided further evidence on the activity of green tea in PC [134].

3.5.38. Helicteres hirsuta Lour

Helicteres hirsuta Lour is the name of a herbal medicine used for the treatment of malaria and diabetes. Terpenoids, flavonoids, and lignans are the dominant constituents of Helicteres species [186]. Pham et al. showed that the leaf and stem extracts from Helicteres hirsuta and their aqueous and saponin-enriched butanol sub-fractions possessed a strong anticancer activity in vitro against MIA PaCa-2, BxPC-3, and CFPAC-1 cells [135].

3.5.39. Inula helenium

Inula helenium is a widespread plant species belonging in the sunflower family asteraceae. It is native in Eurasia, Spain, and Xinjiang Province in western China. The constituents of Inula helenium are sesquiterpene lactones eudesmanolides, having anticancer, anti-inflammatory, antimicrobial, antiproliferative, and cytotoxic properties. Sesquiterpenoids contain thousands of compounds, and have been described as the active components of various medicinal plants used in traditional medicine. Zhang et al. showed that low concentrations of the extract of inula helenium caused cfpac-1 cell cycle arrest, whereas high concentrations induced mitochondria-dependent apoptosis. In addition, ethyl acetate extract of inula helenium inhibited the phosphorylation of the signal transducer and activator of the transcription (stat)3/akt pathway [136].

3.5.40. Lonicera japonica

Lonicera japonica is a species of honeysuckle native to eastern Asia, and has the highest contents of chlorogenic acid [187]. The dried leaves and flowers are used in traditional Chinese medicine to treat fever, cough and thirst, and certain inflammatory disorders, including viral infections. Lin et al. investigated a homogenous polysaccharide extracted and purified from flowers of Lonicera japonica in PC cell lines. They showed that Lonicera japonica inhibited BxPC-3 and PANC-1 PC cell growth at the concentration of 1 mg/mL [137].

3.5.41. Lupeol

Lupeol is a dietary triterpene present in many fruits and medicinal plants. This ingredient possesses a number of pharmacological properties, including in vitro and in vivo anti-cancer activities. Liu et al. [138] showed that Lupeol inhibited the proliferation of PC cells, and induced apoptosis and cell cycle arrest.

3.5.42. Mangifera indica

Mangifera indica, commonly known as mango, is a species of flowering plant in the sumac and poison ivy family Anacardiaceae. Mango components can be grouped into macronutrients (carbohydrates, proteins, amino acids, lipids, fatty, and organic acids), micronutrients (vitamins and minerals), and phytochemicals (phenolic, polyphenol, pigments, and volatile constituents). Mango fruit also contains structural carbohydrates, such as pectins and cellulose. The most important organic acids include malic and citric acids [188]. It has been shown that different parts of the mango tree have different therapeutic properties. Nguyen et al. found that a methanol extract of the bark of Mangifera indica could inhibit the survival of human PC cells under nutrient-deprived conditions without an apparent toxicity. This methanol extract was found to consist of 19 compounds [139].

3.5.43. Mexican Lime (Citrus aurantifolia)

Lime (Citrus aurantifolia Swingle) is a citrus fruit, having antineoplastic properties. Thirty-three chemical compounds were identified, with d-limonene forming the major constituent. Other prominent constituents include 3,7-dimethyl-2,6-octadien-1-ol geraniol E-citral Z-citral and β-ocimene [189]. Patil et al. extracted the bioactive compounds of Mexican lime (neohesperidin, hesperidin, and hesperitin) using different solvents. They showed that limonoids identified (limonexic acid, isolimonexic acid, and limonin) inhibited PC-28 growth. Furthemore, the induction of apoptosis was confirmed by the expression of Bax, Bcl-2, casapase-3, and p53, indicating that antioxidant activity depends on the flavonoids, whereas the inhibition of proliferation depends on the content of both flavonoids and limonoids [140].

3.5.44. Moringa Oleifera

It has previously been described that the combination of Moringa oleifera with radiation excibits an additional inhibitory effect by overcoming the radioresistance of PC cells [61]. In this study, the authors investigated the effect of aqueous Moringa oleifera leaf extract on cultured human PC cells. They found that this extract inhibited the growth of all PC cell lines, and enhanced the cytotoxic effect of cisplatin on PC cell lines [141]. Moringa oleifera leaf extract inhibits the growth of PC cells and the cells’ NF-κB signaling pathway, and increases the efficacy of chemotherapy with cisplatin in human PC cells.

3.5.45. Matrine

Matrine, an alkaloid extracted from the Chinese herb of the genus Sophora flavescens, has exhibited a variety of pharmacological effects, including anti-proliferative and pro-apoptotic properties. Matrine and the related compound oxymatrine act as a nematicide against a variety of nematodes [142]. Liu et al. showed in in vitro assays, that matrine inhibited cell viability by down-regulating the expression of PCNA, and induced cell apoptosis by reducing the ratio of Bcl-2/Bax, up-regulating Fas, and increasing activation of caspases-8, -3, and -9. In the in vivo model, matrine inhibited tumor growth, and regulated the tumoral gene expression [190].

3.5.46. Naringenin and Hesperetin Combined Treatment

Citrus unshiu is a seedless citrus species grown in Japan, Spain, central China, Korea, the USA, South Africa, and South America. The chemical constituents of the Citrus unshiu include γ-terpinene 2-β-pinene 1-methyl-2-isopropylbenzene L-limonene β-ocimene and α-pinene [191]. Lee et al. showed that the combined treatment of naringenin and hesperetin inhibited the growth and the migration of human PC cells compared to separate treatment with naringenin or hesperetin, through the induction of caspase-3 cleavage [143]. Moreover, combined treatment inhibited the phosphorylation of focal adhesion kinase and p38 signaling compared with separate treatment. In in vivo xenograft models, the combination treatment again showed an anti-growth effect.

3.5.47. Nerium oleander

Oleandrin, a cardiac glycoside, exerts an anti-proliferative activity in in vitro malignant cells. PBI-05204, an extract of Nerium oleander containing oleandrin, was tested in a human PC orthotopic model. It was found that all the control mice exhibited tumors, whereas 25% of the mice treated for 6 weeks with PBI-05204 (40 mg/kg) showed dissectible tumors. PBI-05204 also markedly enhanced the antitumor efficacy of gemcitabine. This novel botanical drug exerts its potent antitumor activity through down-regulation of PI3k/Akt and mTOR pathways [144].

3.5.48. Nimbolide

Nimbolide is a triterpenoid extracted from the flowers of Azadirachta indica, which is a tree native to the Indian subcontinent. It represents a major component in Siddha and Unani medicine. Products made from this tree have been used in India for their anthelmintic, antifungal, antidiabetic, antibacterial, antiviral, contraceptive, and sedative properties. Neem leaves have also been used for various skin disorders, such as eczema and psoriasis. In adults, short-term use is probably safe, although long-term use may be toxic for the liver and kidneys. Subramani et al. assessed the anticancer properties of nimbolide against PC. They showed that nimbolide induces the generation of reactive oxygen species, thereby regulating both apoptosis and autophagy in PC cells. Nimbolide-mediated reactive oxygen species generation inhibited proliferation and metastasis via mitochondrial-mediated apoptotic cell death. In in vivo experiments, nimbolide was effective in inhibiting PC growth and metastasis [145].

3.5.49. Obacunone

Obacunone is one of the oxygenated triterpenoids found in rutaceae family. It has many biological actions, including antiproliferative activities against cancer cells. Chidambara et al. investigated the antiproliferative action of obacunone on cultured PC cells. The plant induced the inhibition of Panc-28 cell proliferation in a dose- and time-dependent manner, with a concurrent induction of apoptosis. The plant was able to up-regulate the expression of p53 and pro-apoptotic protein Bax, and down-regulate the Bcl2, NFκB, and Cox-2 [146].

3.5.50. Ocimum sanctum

Ocimum sanctum (“Holy Basil”) has been used in traditional Indian medicine in a variety of clinical situations. The chemical composition of Holy Basil, also known as tulsi, is highly complex, containing many nutrients and other biologically active compounds, the proportions of which may vary considerably [192]. Shimizu et al. showed that extracts of Ocimum sanctum leaves can inhibit the proliferation, migration, invasion, and induce apoptosis of PC cells in vitro. Intraperitoneal injections of the aqueous extract of Ocimum sanctum inhibited the growth of orthotopically transplanted PC cells. Mice treated with Ocimum sanctum extracts exhibited up-regulation of E-cadherin, and induction of apoptosis, whereas genes that promote survival and chemo/radiation resistance were down-regulated [147].

3.5.51. Oleuropein

Olea europaea L. leaves are an agricultural waste product with a high concentration of phenolic compounds, especially oleuropein. Oleuropein has a significant anti-proliferative activity. Goldsmith et al. showed that the extracts of the Corregiola and Frantoio varieties of Olea europaea L. leaves significantly decreased the viability of PC cell lines relative to controls [148].

3.5.52. Olive Biophenols (Oleuropein, Hydroxytyrosol, and Tyrosol)

Olives contain more than 100 different biophenols, the most important being hydroxytyrosol and tyrosol, as well as their secoiridoid derivatives, verbascoside, lignans, and flavonoids. The main pharmacological studies reported so far have dealt with the antioxidant, anti-inflammatory, cardiovascular, immunomodulatory, gastrointestinal, respiratory, antimicrobial, anticancer, and chemopreventive properties of these biophenols. As far as their safety is concerned, these products are generally considered safe, although further studies are needed. The olive biophenols, oleuropein, hydroxytyrosol, and tyrosol, showed cytotoxicity towards cancer cells without affecting normal cells. In a recent study, the authors treated PC cells and non-tumorigenic pancreatic cells with oleuropein, hydroxytyrosol, and tyrosol. They found that oleuropein displayed selective toxicity towards MIA PC cells and hydroxytyrosol towards MIA PC and HPDE cells. Furthemore, oleuropein and hydroxytyrosol induced apoptosis in MIA PC cells [149].

3.5.53. Oridonin

Oridonin is an organic heteropentacyclic compound isolated from the leaves of the herb Rabdosia rubescens. It is an organic heteropentacyclic compound, an enone, a cyclic hemiketal, a secondary alcohol, and an ent-kaurane diterpenoid (Figure 6). This traditional Chinese medicine substance has been shown long ago to exhibit antitumor effects.

Figure 6

Chemical structure of Oridonin (PubChem 134688823).

Bu et al. found that oridonin induced apoptotic cell death in PC cells in a dose-dependent manner; the p53 being responsible for this antineoplastic action. Oridonin also increased the expression of p-p53 and p21 in the PC cells [150]. To further verify the anti-cancer effects of oridonin, Gui et al. showed that 105 miRNAs were differentially expressed in oridonin-treated BxPC-3 human PC cells, indicating that oridonin inhibits BxPC-3 cells through regulating the expression of miRNAs [151].

3.5.54. Paeonia lactiflora

The chemical compound aeoniflorin, a monoterpene glycoside, represents one of the major constituents of an herbal medicine derived from Paeonia lactiflora. Aeoniflorin has been shown to exhibit antitumor effects in various cancer types. Li et al. showed that Aeoniflorin suppressed the growth of PC cell lines, and sensitized them to X-ray irradiation. Aeoniflorin treatment resulted in a reduction of cell proliferation, and an increase in the expression of the apoptotic protein Bax [152]. These results suggest that Aeoniflorin inhibits PC growth by up-regulating the tumor-suppressor gene HTRA3.

3.5.55. Palm Oil Phenolics and PALM JUICE

Palm oil and its components are increasingly used in foods such as cooking oils, margarines, shortenings, and confectionery products. It contains 50% saturated fatty acids, 40% monounsaturated fatty acids, and 10% polyunsaturated fatty acids [193]. Oil palm phenolics have been shown to have anti-carcinogenic activities. By using two PC cell lines, Ji et al. showed that oil palm phenolics suppressed PC cell proliferation. Oil palm phenolic-induced apoptosis was associated with a decrease in Bcl-XL expressions, and increased cleaved caspase-3, caspase-9, and PARP expression, thus confirming the anti-tumor effects of these substances [153].

3.5.56. Paramignya trimera Root and Phyllanthus amarus

During recent years, a medicinal plant rich in saponins (more than 500 mg EE/g dried sample) named Xao tam phan (Paramignya trimera Guillaum) has been used in cancer prevention and treatment [154]. Phyllanthus amarus, a small herb belonging to the family Euphorbiaceae, is used widely, especially in Indian Ayurvedic medicine, for a number of pathological conditions [155]. Nguyen et al. assessed the cytotoxic activity of extracts and fractions from the Paramignya trimera root and Phyllanthus amarus against two PC cell lines. The root of Paramignya trimera root and the whole plant of Phyllanthus amarus were used. The findings revealed an impressive cytotoxic capacity of the Paramignya trimera root extract against both PC cell lines in a range of concentrations, which was higher than those of gemcitabine. In contrast, the cytotoxic capacity of the Phyllanthus amarus extract was significantly lower than that of gemcitabine. The IC₅₀ values of the Paramignya trimera root extract were lower than that of the Phyllanthus amarus extract [156]. Paramignya trimera root extract could be a source for the development of new drugs against PC.

3.5.57. Plumbagin

Plumbagin, isolated from Plumbago zeylanica, possesses an anticancer activity. The structure of its active principle is similar to that of vitamin K [194]. Plumbagin inhibited the growth of Panc-1 and Bxpc-3 cells by inducing apoptosis through the mitochondria-related pathway and caspase cascades [157].

3.5.58. Pomegranate extract

Pomegranate extract is a standardized whole-fruit extract of pomegranate, which is a fruit rich in polyphenols, organic acids, sugars, polysaccharides, and minerals [195]. This extract exhibits strong antioxidant activity, having anticancer properties also. Nair et al. used PANC-1 and AsPC-1 human PC cells to test the effects of Pomegranate extract. It was shown that Pomegranate extract induced cell cycle arrest, and inhibited cell proliferation in PANC-1 cells. It is of interest that Pomegranate extract was more effective in inhibiting the proliferation of PANC-1 cells than the clinically used dose of paclitaxel [158]. It is possible that unidentified phytochemicals are responsible for the inhibitory effect of Pomegranate extract.

3.5.59. Pulsatilla koreana

Pulsatilla koreana has been used as a traditional medicine for the treatment of a number of pathological situations in Korea. Phytochemical studies demonstrated the presence of protoanemonin, deoxypodophyllotoxin, oleanane, and 33 upine-type triterpenoid saponins on Pulsatilla koreana roots [196]. Son et al. showed that SB365 (saponin D isolated from the root of Pulsatilla koreana) suppressed the growth and proliferation of human PC cell lines by inducing apoptosis through an increase in the levels of cleaved caspase-3, and a decrease in the Bcl-2 expression. SB365 exerted also a significant anti-angiogenic effect. Finally, SB365 inhibited tumor growth through the induction of apoptosis, and inhibition of angiogenesis in an in vivo mouse xenograft [159].

3.5.60. Quercetin

Quercetin represents one of most effective biopolyphenols chemicals present in several plants that have antioxidative and anti-inflammatory actions. Quercetin has been used as an adjunctive drug to PC treatment, acting through inhibition of autophagy and apoptosis oxidative stress, and enhancing the sensitivity to chemotherapy agents [160]. Borska et al. demonstrated that quercetin exerted cytotoxic action on two neoplastic cell lines. In the EPP85-181RDB cell line, quercetin sensitized resistant cells to daunorubicin, suggesting that it could break the resistance of neoplastic cells to chemotherapy [161]. This synergistic effect might allow the reduction in the total dose of the antineoplastic drug, thus reducing the rate of possible treatment side-effects. It can be used, therefore, as a supplementary drug to patients with PC.

3.5.61. Radix Scutellariae

Radix Scutellariae represents the dried root of Scutellariae baicalensis Georgi. This plant has been extensively used in several Asian countries as an effective antinflammatory agent. Its root, known as Radix Scutellariae, is the source of the Chinese medicine Huang Qin for various clinical disorders. The main compounds responsible for the biological activity of skullcaps are flavonoids. Six flavones have proven to be the major bioactive flavones existing in the forms of aglycones and glycosides [162]. In a recent study, Liu et al. investigated the mechanisms of the total flavonoid aglycone extracted from Radix Scutellariae in inducing autophagy and apoptosis in PC cells in vitro and in vivo. In the in vitro experiments, they showed that total flavonoid aglycone extracted exhibited an anti-tumor activity, and induced apoptosis and autophagy in PC cell lines through the PI3K/Akt/mTOR signaling pathway. In the in vivo studies, they showed that 150 mg/kg of total flavonoid aglycone extracted inhibited the BxPC3 tumor growth in immune deficient mice, and induced both apoptosis and autophagy [163].

3.5.62. Rhazya stricta

Rhazya stricta Decne is an important medicinal species used in South Asia and Middle East. Some of its alkaloids have been reported to have anticancerous properties. The study of Shaer et al. showed that the crude alkaloids extract of Rhazya stricta significantly induced apoptotic death in PC cells. They observed a significant decrease in cell viability in a dose-dependent manner [197].

3.5.63. Salvia chinensis

Salvia chinensis is an annual plant growing in China belonging to the Labiatae plant family. This herbal medicine has been used in the treatment of hepatitis, as well as in breast, liver, and gastric cancer. Salvia chinensis consists of more than fifty chemical constituents, in four classes, namely terpenoids, phenolic acids, flavonoids, and dibenzylcyclooctadiene lignans [164]. Zhao et al. demonstrated that Salvia chinensis induced potent cytotoxicity in the MiapaCa-2 human PC cells. Under fluorescence microscopy, morphological features of apoptosis in the PC cell lines following treatment with the extract were also detected [165].

3.5.64. Sedum sarmentosum Bunge

Sedum sarmentosum Bunge extract, a traditional Chinese herbal medicine, contains multiple active chemical components, including tricin-7-O-b-dglucoside, isorhamnetin, quercetin, and kaempferide [198]. This herbal has been used in a variety of clinical disorders, including liver diseases and other inflammatory situations. It has recently been used to treat tubulointerstitial damage in kidneys following injury [199]. However, the role of this extract has never been tested in PC. In this regard, Bai et al. showed that the Sedum sarmentosum Bunge extract inhibited cell growth, accompanied by down-regulated expression of proliferating cell nuclear antigen, and increased cellular apoptosis in a mitochondrial-dependent manner. Moreover, Sedum sarmentosum Bunge extract induced p53 expression, and inhibited epithelial-mesenchymal transition through down-regulation of the proliferation-related hedgehog signaling pathway. In animal xenograft models of PC, Sedum sarmentosum Bunge extract suppressed the growth of pancreatic tumors [166].

3.5.65. Sugiol

Sugiol is an abietane diterpenoid natural product acting as an antiviral and antineoplastic agent, and as an antioxidant and radical scavenger. Hao et al. evaluated the anticancer activity of sugiol, and observed that sugiol reduced the cell viability of human PC cells through reactive oxygen species-mediated alterations in mitochondrial membrane potential, ultimately leading to apoptosis. Sugiol also caused cell cycle arrest in the G2/M phase, and up-regulated the expression of Bax, with down-regulation of Bcl-2 expression, indicating that it could be a potent molecule against PC [167].

3.5.66. TEOA (2a,3a,24-thrihydroxyurs-12-en-28-oicacid)

TEOA (2a,3a,24-thrihydroxyurs-12-en-28-oicacid) a traditional Chinese herbal medicine which represents a pentacyclic triterpenoid isolated from the roots of A. eriantha Benth, exhibiting anti-inflammatory and anti-cancer effects both in vivo and in vitro. Recently, Yang et al. demonstrated that this herbal inhibited the proliferation and migration of PC cells concurrently, causing the induction of mitochondrial dysfunction in PANC1 and SW1990 cells. Finally, TEOA induced autophagic cell death in PC cells by inactivating the ROS-dependent mTOR/p70S6k signaling pathway [168].

3.5.67. Toosendanin

Toosendanin is a triterpenoid extracted from Melia toosendan Sieb et Zucc, used as a digestive tract-parasiticide in ancient China. Toosendanin has a marked antibotulismic effect both in vivo and in vitro. Finally, Toosendanin can induce apoptosis in several cell lines, and suppress the proliferation of various human cancer cells [169]. Pei et al. found that toosendanin suppressed the viability and growth, as well as the migration and invasion of PC cells. Furthermore, toosendanin repressed xenograft tumor growth in mouse PC models. The substance has no significantly toxic side-effects. Toosendanin inhibits PC cell growth by blocking the Akt/mTOR signaling pathway [170].

3.5.68. Tripterygium wilfordii

Tripterygium wilfordii Hook F is a vine plant, used widely in China as a herbal medicine. The main bioactive ingredients of Tripterygium wilfordii may be alkaloids, which, may account for its pharmacological properties. This herbal has anti-inflammatory, anticancer, and antibacterial activities, as well as beneficial effects on immune disorders. Zhao et al. recently performed network pharmacology on Tripterygium wilfordii Hook F using Traditional Chinese Medicine Systems Pharmacology and Gene Cards databases [171]. They screened out 22 ingredients and 25 target genes associated with PC. They found that triptolide-plasminogen activator urokinase could represent a novel target for patients with PC.

3.5.69. Valtrate

Valtrate, also known as valtric acid, is a novel epoxy iridoid ester isolated from the Chinese aromatic medicinal herb Valeriana jatamansi Jones, belonging in the class of organic compounds known as iridoids and derivatives [200]. It has been utilized for medicinal purposes in China and India for many years. Chen et al. showed that valtrate inhibited the growth of PC cells by inducing apoptosis and cell cycle arrest. Moreover, valtrate inhibited the tumor growth of the PC cell PANC-1 in xenograft mice by 61%. The underlying mechanisms include an increase of the expression of Bax, suppression of Bcl-2, c-Myc and Cyclin B1, inhibition of the transcriptional activity of Stat3, and decrease in the expression of Stat3 [172].

3.5.70. Xanthohumol

Xanthohumol is a natural product found in the female inflorescences of Humulus lupulus, also known as hops. It is a member of the class of chalcones that is trans-chalcone substituted by hydroxy groups at positions 4, 2′, and 4′; a methoxy group at position 6′; and a prenyl group at position 3′ [201]. Jiang et al. showed that xanthohumol inhibited the growth of PC cells and their xenograft tumors by inducing cell cycle arrest and apoptosis via inhibition of phosphorylation of the signal transducer, activation of the transcription 3, and expression of its downstream-targeted genes cyclinD1 and Bcl-xL. Xanthohumol might be a promising therapeutic agent against PC. The STAT3 signaling pathway is its key molecular target [173].

3.5.71. Xao tam phan (Paramignya trimera)

Xao tam phan (Paramignya trimera) is a traditional medicinal plant used in the treatment of a number of cancers in Vietnam. This plant contains saponins, phenolics, flavonoids, and proanthocyanidins equiv., 81.49 mg rutin equiv., and 58.08 mg catechin equiv. (per g dried extract, respectively) [202]. Chemical analysis of Paramignya trimera leaves showed that total phenolic, total flavonoid, proanthocyanidin, and saponin contents were gallic acid, protocatechuic acid, ellagic acid, rutin, and quercetin. Powdered extract of the Paramignya trimera leaf exhibited anti-proliferative capacity against PC cell lines, being higher than those of ostruthin and gemcitabine. Paramignya trimera leaf extract represents a rich source of phytochemicals that possess antioxidant and anti-proliferative activities against PC [174].

3.5.72. Xylaria psidii

Xylaria is a genus of ascomycetous fungi growing on dead wood. It represents an important source of biologically active metabolites. Two compounds, isolated from Xylaria psidii, namely xylarione A and 5-methylmellein, exhibited cytotoxicity against PC cells, with features characteristic of apoptosis. The cell cycle distribution confirmed a cell cycle arrest at the sub-G1 phase. Flow cytometry analysis displayed a substantial loss of mitochondrial membrane potential by both the compounds [175]. The isolated compounds from Xylaria psidii, namely xylarione A and 5-methylmellein, may serve as potential therapeutic agents for PC.

3.5.73. Wikstroemia indica

Wikstroemia indica is a small shrub with small flowers and toxic fruits. It can be found in forests and on rocky, shrubby slopes in central and southeastern China, Vietnam, India, and the Philippines. It is an herb that has been used for a long time in traditional Chinese medicine. Four compounds, namely daphnoretin, chrysophanol, myricitrime, and rutin, were purified from Wikstroemia indica [203]. It has some side-effects, including dizziness, blurred vision, nausea, vomiting, abdominal distension and pain, and diarrhea. This plant has been used in clinical practice as an antipyretic, detoxicant, and expectorant. Chang et al. evaluated the in vitro cytotoxicity against PC cell lines of 26 compounds isolated from the roots of Wikstroemia indica. Two compounds, namely 8 and 12, displayed preferential cytotoxicity in the nutrient-deprived medium, without causing toxicity in normal nutrient-rich conditions [176].