1. INTRODUCTION

Based on statistics from 2016, breast cancer is the most common cancer among women in the United States, making up 29% of all newly diagnosed cancers in that year alone. It is also the second most common cause of cancer-related deaths, after lung and bronchial cancers [1]. Depending on the stage of breast cancer, hormone receptor levels or function and the patient’s general health, surgery (e.g., lumpectomy or mastectomy), radiation therapy, hormone or endocrine therapy using tamoxifen or aromatase inhibitors, chemotherapy, and targeted therapy are currently the most common anticancer treatments provided [2].

There are serious side effects associated with each treatment which led an interest among scientists to increasingly investigate the potential anticancer effects of natural products including medicinal plants. A study has shown that 30-50% of breast cancer patients have continuous pain in the area of their breast and in their arm and shoulder 3-5 years after undergoing surgery and radiotherapy. Furthermore, 15-25% of these patients have lymphedema, and another 35% have claimed to have shoulder and arm movement limitations [3]. The administration of tamoxifen as a standard endocrine therapy has increased the risks of endometrial carcinoma, thromboembolism, and tamoxifen resistance due to its antiestrogenic effects [4]. In addition, tamoxifen causes vaginal bleeding, discharge or dryness, and hot flushes resulting from its antiestrogenic effects. Aromatase inhibitors, on the other hand, have been shown to increase the risks of bone fractures compared with the effects of tamoxifen because estrogen has a protective effect against osteoporosis [5].

Information on the natural products discussed in this review was obtained by searching the PubMed, ISI Web of Science, and Google Scholar databases using different terms, which include the keywords “natural products,” “breast cancer,” “Asia,” and “Malaysia” combined with the Boolean operators “AND” and “OR.” There were no language or search-year restrictions. Based on the search, several medicinal plants that have been shown to have potential beneficial therapeutic effects against breast cancer in Asian countries such as Aloe vera, Alpinia galangal, Centella asiatica, Andrographis paniculata, Curcuma longa, Morinda citrifolia, Trigonella foenum-graecum, Zingiber officinale, Pereskia bleo, and Typhonium flagelliforme are reviewed.

2. A. VERA

A. vera, or Aloe barbadensis (Miller), which is a member of the Liliaceae family, has been shown to have curative or healing effects. A. vera extract exhibits important biological activities including anticancer, antioxidant, immunoprotective, hypoglycemic, hypolipidemic, and antifungal properties [6-9]. A. vera exhibits antineoplastic effects by inducing apoptosis and modulating the expression of effector molecules such as down-regulating cyclin D1, CYP 1A1, and CYP 1A2, and up-regulating Bax and p21 expression, in breast cancer cells [10]. A. vera leaf extract has been shown to exhibit significant inhibitory effect on breast cancer cells by changing the antioxidant and detoxification enzyme activity levels [11].

3. A. GALANGAL

A. galangal, known locally as “galangal” or “lengkuas,” is commonly used in Southeast Asian countries including Malaysia, Thailand, and Indonesia. For centuries, the rhizome of this plant has been commonly used as food flavoring and medication. Traditional medical practices such as Ayurveda, Unani, Chinese, and Thai folk medicine have used A. galangal as a part of their medical system [12]. The active compound in galangal, identified as [E]-8 beta, 17-epoxylabd-12-ene-15, 16-dial [1], and also known as dipertine-1, has been reported to possess antifungal [13] and antitumor activities [14,15]. A. galangal extract possesses bioactive compounds such as flavonoids (kaempferol, kaempferide, and galangin), terpenoids (10-acetoxychavicol acetate, 10-acetoxy eugenol, galanal A, galanal B, and galanolactone), and phenolic acids. These compounds have been demonstrated to have proapoptotic effects and to inhibit the proliferation of a breast cancer-derived cell line [16]. However, it has been found that A. galangal extract from Malaysia is less cytotoxic toward MCF7 breast cancer cell line than A. galangal extract originating from Thailand [17]. It is plausible that this difference in cytotoxicity is due to the higher levels of 1’-acetoxychavicol acetate in the sample from Thailand, which could be a result of ecological variations and differences in the times of collection [18].

4. C. ASIATICA

C. asiatica, which is locally known as “pegaga” and found in wet areas in many Asian countries, is one of the common plants traditionally used for treating several types of ailments. C. asiatica is a medicinal plant that contains triterpene glycosides such as centellasaponin, asiaticoside, sceffoleoside, and madecassoside [19], as well as terpenoids such as madecassic and asiatic acids [20,21]. A study on the effect of C. asiatica on breast cancer cells indicated the presence of apoptosis as shown by nuclear condensation, increased annexin staining, loss of mitochondrial membrane potential, and induction of DNA breaks [22]. Moreover, the presence of phenolic and flavonoid constituents in C. asiatica extract suggests antioxidant activities and potential antitumor effects against breast cancer [23,24]. The combined use of asiaticoside and the chemotherapeutic agent vincristine on MCF-7 and its ADM-resistant line (MCF-7/ADM) cells has been shown to have a synergistic effect, inducing apoptosis and increasing the antitumor activity of vincristine in cancer cells compared with asiaticoside alone and vincristine alone which provides useful information for developing new cancer chemotherapies [25].

5. A. PANICULATA

A. paniculata is an important herbal medicine that has been used for centuries in many Asian countries including India, China, Thailand, and Malaysia. The plant is found in moist and shady areas. Locally, it is known as “hempedu bumi.” The leaves and stems (the parts most often used) have been reported to contain diterpenes, flavonoids, and stigmasterol [26]. The anticancer activity of the dichloromethane fraction of A. paniculata methanolic extract has been reported [27]. Andrographolide is a natural diterpenoid lactone isolated from A. paniculata, and it shows inhibitory effects, by causing cell cycle arrest during the G0/G1 phases, inducing cell cycle inhibitory protein p27 expression and reducing the expression of cyclin-dependent kinase 4 in breast cancer cell lines [28]. Benzylidence, a derivative of andrographolide also has been reported to show its inhibitory effects by inducing of G1 arrest and apoptosis in cancer cells [29]. Hypoxia is common in breast cancer and results from the tumor outgrowing and the ability of the existing vasculature to supply the tissue with oxygen [30]. To adapt this hypoxic environment, the levels of hypoxia-inducible factors are increased, leading to the induction of angiogenesis, cell proliferation, invasion, and metastasis [31]. Andrographolide is able to inhibit hypoxia-inducible factor-1 expression in breast cancer cell lines, highlighting the potential effects of andrographolide in treating breast cancer [32]. A. paniculata can induce DNA fragmentation and increase the frequency of apoptosis in human breast cancer cell lines in both time- and concentration-dependent manners through increased p53 Bax and caspase-3 expression, and reduced bcl2 expression [33].

6. C. LONGA

C. longa is a well-known tropical herb, which grows abundantly in Asia and is locally known as “turmeric” or “kunyit” in Malaysia. It is commonly used in cooking to flavor foods and to give color to dishes due to its rich yellow color, and it is occasionally eaten raw. Curcumin, the active ingredient in turmeric, is found in the plant’s rhizome. Curcumin has been shown to promote cell cycle arrest and apoptosis at the G2/M phase of cell proliferation by inhibiting the dynamic assembly of microtubules through mitotic checkpoint activation in MCF-7 cells [34]. Curcumin inhibits Ki-67 expression and increases levels of proliferating cell nuclear antigen and p53 mRNAs in breast cancer cells [35]. It also inhibits β-catenin, cyclin D1, and Slug expression in MDA-MB-231 and MCF-7 cells, suggesting that it may inhibit the abnormal activation of the Wnt/β-catenin signaling pathway that is commonly associated with breast cancer. Curcumin also inhibits MCF-7 cell adhesion and invasion by down-regulating urokinase-type plasminogen activator protein expression through NF-κB activation [36].

7. M. CITRIFOLIA

M. citrifolia is a plant commonly found in Southeast Asia, especially in Malaysia. Much research has been conducted to investigate the health benefits of all parts of the plant, including the fruits (called “noni fruit”), leaves, bark and roots, which have been shown to contain several active compounds with high medicinal value. Its fruit juice inhibits proliferation, increases apoptotic cell cycle arrest, reduces intracellular generation of reactive oxygen species, and ameliorates mitochondrial membrane potentials in MCF-7 and MDA-MB-231 breast cancer cell lines [37]. It also inhibits aromatase enzyme, indicating its potential in the treatment of breast cancer [38].

8. T. FOENUM-GRAECUM

T. foenum-graecum, which is primarily produced in India, is extensively used in the traditional Indian medical system for treating various diseases. This herb is also used in Malaysia as a spice for culinary purposes [39]. Its seeds, locally known as “fenugreek” or “halba,” have been reported to possess antibacterial, galactagogue, and carminative properties. T. foenum-graecum induces apoptosis in MCF-7 human breast cells [40,41] but not in normal cells [42,43].

9. Z. OFFICINALE

Z. officinale is used worldwide as flavoring agent and spice, and is locally known as “ginger” or “halia.” The chemical [6]-gingerol (1-[4′-hydroxy-3′methoxyphenyl]-5-hydroxy-3-decanone) found in its rhizome is a pungent phenolic ingredient that possesses antiinflammatory, antihepatotoxic, and anticardiotoxic effects, as well as antioxidant properties [44]. Cell adhesion, invasion, motility, and metastasis have been shown to be inhibited by [6]-gingerol in human breast cancer cell lines [45]. In addition, the proliferative and colony-forming abilities of breast cancer cell lines are suppressed by [6]-gingerol. Apoptosis, loss of cell viability, chromatin condensation, DNA fragmentation, caspase 3 activation, and poly (ADP-ribose) polymerase cleavage have also been found following [6]-gingerol treatment [46]. Furthermore, it inhibits proliferation in breast cancer lines without affecting normal mammary epithelial cell lines [47], indicating its safety in humans.

10. P. BLEO

P. bleo has been traditionally used for medicinal purposes in Asian countries including Malaysia. It is also known as “jarum tujuh bilah” and belongs to the Cactaceae family. This plant is believed to treat various diseases such as cancer, rheumatic conditions, ulcers, diabetes, and hypertension. Methanolic extracts from the combined stems and leaves of P. bleo contain several bioactive compounds that can cause apoptosis in breast cancer cells through the activation of caspase-3 and c-myc pathways [48]. In addition to their cytotoxic activities against MCF 7 breast cancer cell lines, the leaves of the plant (both crude methanolic extracts and ethyl acetate fractions) do not exhibit any cytotoxicity to normal human fibroblast cell lines [49]. The plant also contains Vitamin E (?-tocopherol), which has antioxidant [50], antiproliferative, and anticancer properties [51], making it a useful herb that should be further investigated in controlled clinical trials as a possible therapeutic agent against breast cancer. However, the plant’s leaves (methanolic and aqueous extracts) and stem (crude methanolic and fractionated ethyl acetate, t-butanol, and aqueous extracts) do not show any significant antiproliferative effects against the murine mammary cancer (4T1) and normal murine fibroblast (NIH/3T3) cell lines [51,52]. The inconsistency of these findings may be due to the use of different cell lines and plant parts (stem and leaves) which may contain different bioactive compounds. Therefore, additional studies on the effectiveness of P. bleo against breast cancer cells should be investigated due to its potential anticancer property.

11. T. FLAGELLIFORME

T. flagelliforme is commonly known as “Keladi Tikus” or “Rodent Tuber” by Malaysians. The tuber of the plant has been traditionally used to treat cancer. Several studies have confirmed its antioxidant and pain-relieving property, and its potential to prevent metastasis in various types of cancer cells such as breast, cervical, nasopharyngeal, prostate, pancreatic, and lung cancer lines [53,54]. The tuber contains an active protein called lectin, which has anticancer and antiproliferative properties. This may be due to the difference in the sugar component of the glycoproteins on the surface of cancer cells relative to those on normal cells, which may result in different effects of lectin at the cell surface [55]. The tuber of T. flagelliforme has been found to have a stronger cytotoxic effect on breast cancer cell than on cervical cancer cells [56].

These medicinal plants, which are available in Asian countries, as well as their active compounds and mechanisms of action against breast cancer, are summarized in Table 1.

Table 1: Medicinal plants from Asian countries with potential activity against breast cancer. [Click here to view]

12. ADVERSE EFFECTS AND DRUG-NATURAL PRODUCT INTERACTIONS

Natural products have always been assumed or believed to be safe because they are “natural.” However, this assumption is not necessarily valid because many modern therapies are synthesized from natural products or contain chemicals that are structurally similar to those derived from natural products including medicinal plants. In addition, many natural products are not rigorously tested in standardized clinical trials compared with how modern or conventional medications are evaluated [57]. Some problems may also emerge when using natural products together with chemotherapeutic agents because of the likelihood of a drug-natural product interaction. For example, increased skin sensitivity toward radiation therapy, irregular blood pressure, and problems with anesthetic agents used during surgery have been reported when drugs and natural products have been used together [58].

Bajwa and Panda [59] have reported on several plants that can be a significant concern to anesthesiologists, for example, products derived from Echinacea purpurea, Ephedra vulgaris, Allium sativum, Ginkgo biloba, Ginseng, Valerian officinalis, Z. officinale, Tinospora cordifolia, and C. longa. Furthermore, many plant metabolites have not been fully investigated, and they can potentially act as carcinogens and may disturb cellular metabolic processes in the body [60].

There is a chance of herb-drug interactions between the various active constituents of A. vera and other drugs in patients who are simultaneously prescribed several medications. For example, prostaglandin synthesis may decrease, which can result in the secondary aggregation of platelets [61]. In a case report, a 35-year-old woman lost 5 L of blood during surgery for hemangioma following A. vera consumption (4 tablets/day for 2 weeks before admission), which was suspected to be caused by an interaction between A. vera and sevoflurane [62]. Another patient presented with severe acute hepatitis following A. vera consumption. The woman, who had consumed A. vera tablet (500 mg) approximately for 4 weeks before being admitted to the hospital, presented with progressive jaundice, pruritus, alcoholic bowel movements, and abdominal discomfort [63], indicating that additional studies should be conducted on A. vera-drug interactions. Regardless of its wound-healing and emollient properties, A. vera has also been shown to cause contact dermatitis, photodermatitis, and erythema after topical applications of A. vera gel [64-66]. Oral consumption of A. vera may cause serious side effects such as diarrhea, hepatitis, laxative-dependency or worsening of constipation, abdominal cramps, and the production of red urine [66].

A. galangal has been reported to be a safe plant because no toxicity has been reported when orally administered to mammals up to the dose of 300 g/kg [67]. C. asiatica has been shown not to cause any toxicity when administered orally if consumed at recommended doses. However, when applied externally, burning sensations and skin allergies have been reported in addition to headache, nausea, dizziness, stomach upset, and serious drowsiness that tend to occur at high doses [68]. Patients who take medications that can cause reductions in sleep or anxiety are advised to avoid this herb as it causes sedation at high dose [69,70], however, to date, no reports are available regarding its interaction with those medications.

A. paniculata has also been reported to be a safe medicinal plant. A study was conducted to investigate potential toxic effects of dried A. paniculata extract on the testis of male Sprague Dawley rats over 60 days. No subchronic testicular toxicity was detected following its administration at doses of 20, 200, or 100 mg/kg [43]. In addition, the adverse effects reported in clinical trials are moderate, occasional, and short term, which include fatigue, allergic reactions, headaches, lymph node pain, lymphadenopathies, diarrhea, nausea, and metallic tastes [71].

C. longa has been extensively used for medicinal purposes, administered either topically, orally, or through inhalation. Curcumin at doses of 800-2500 mg/day for 3 months is safe in a human trial [72]. Furthermore, turmeric at 2.25 g/kg and alcoholic turmeric extract at 300 mg/kg do not cause adverse effects on liver, kidney, and heart [73].

A study conducted on human subjects who consumed 750 mL/day of M. citrifolia juice for 28 days is found to have no toxic effects on major organs including liver [74]. Nevertheless, some adverse events such as a headache, coughing, nausea, menstrual cramps, nasal discharge, stomachache, toothache, sore throat, vomiting, increased bowel movements, as well as upper respiratory and urinary tract infections were observed in subjects who consumed the fruit juice [75,76].

Z. officinale may show some antiplatelet effects [77], and therefore, patients who take heparin, aspirin, and related agents should avoid any products containing this herb. However, a study conducted on rats administered T. foenum-graecum modified diet (5, 10, and 20%) for 90 days showed that they had comparable hematological parameters, histological findings, liver function, and feed efficiency ratios when compared with animals in control group [78]. T. foenum-graecum is also non-toxic to fibroblast cells at a dose of up to 100,000 ng/mL and therefore has the potential for being useful in treating breast cancer [55].

P. bleo up to the doses of 2500 mg/kg does not cause significant changes in behavior such as ataxia, hyperactivity, or hypoactivity in mice after a 2-week observation period. It increases body weight, but no toxicity is observed in the mice [79]. Moreover, P. bleo extract does not have cytotoxic effect on normal MRC-5 cells [80].

13. CHALLENGES, FUTURE PERSPECTIVES, AND CONCLUSION

Many challenges exist when utilizing plants in treating breast cancer. Variations in the geographical location of the plants and the time they are collected increase the variability in the findings of studies on these products, making the comparison of data from across the globe challenging. The utilization of different plant parts (roots, stems, fruits, and leaves) further increases the variability of the data obtained.

The use of medicinal plants as adjuvants remains an approach that could have vast potential for providing additional treatment options, and this potential should be explored in the future. In addition, new technologies that can combine chemistry with high-throughput screening may help facilitate the production of new synthetic drugs that are based on plants and that can act as templates for the production of novel-targeted compounds. The advancement of technologies, including those that can aid in the identification of new genes involved in the reaction to these compounds in performing gene expression studies, may help facilitate this process.

Overall, although the use of medicinal plants as anticancer agents has shown good potential, not only in the Western countries but also in Asian countries, data from controlled clinical trials in humans are still lacking. Since not all natural products including plants should be assumed to be safe, more scientific investigations, which examine appropriate dosing, product efficacy, and their adverse effects, should be conducted. This will allow informed decisions to be made by the patients and medical practitioners.

14. ACKNOWLEDGMENT

This review is funded by Research University Grant from Universiti Sains Malaysia (1001/PPSP/853005).

15. REFERENCES

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-30.

2. National Cancer Institute. Types of Treatment, 2017. Available from: http://www.cancer.gov/about-cancer/treatment/types. [Last accessed on 2017 Dec 15].

3. Ewertz M, Jensen AB. Late effects of breast cancer treatment and potentials for rehabilitation. Acta Oncol 2011;50:187-93.

4. Carpenter R, Miller WR. Role of aromatase inhibitors in breast cancer. Br J Cancer 2005;93 Suppl 1:S1-5.

5. Lonning P, Geisler J, Krag L, Ottestad L, Bremnes Y, Hagen A, et al. Effect of exemestane on bone: A randomized placebo-controlled study in postmenopausal women with early breast cancer at low risk. Proc Am Soc Clin Oncol 2004;23:6.(Abstract 518).

6. Hu Y, Xu J, Hu Q. Evaluation of antioxidant potential of Aloe vera (Aloe barbadensis miller) extracts. J Agric Food Chem 2003;51:7788-91.

7. De Rodrıguez DJ, Hernández-Castillo D, Rodrıguez-Garcıa R, Angulo-Sánchez J. Antifungal activity in vitro of Aloe vera pulp and liquid fraction against plant pathogenic fungi. Ind Crops Prod 2005;21:81-7.

8. Xiao B, Guo J, Liu D, Zhang S. Aloe-emodin induces in vitro G2/M arrest and alkaline phosphatase activation in human oral cancer KB cells. Oral Oncol 2007;43:905-10.

9. Kim K, Kim H, Kwon J, Lee S, Kong H, Im SA, et al. Hypoglycemic and hypolipidemic effects of processed Aloe vera gel in a mouse model of non-insulin-dependent diabetes mellitus. Phytomedicine 2009;16:856-63.

10. Hussain A, Sharma C, Khan S, Shah K, Haque S. Aloe vera inhibits proliferation of human breast and cervical cancer cells and acts synergistically with cisplatin. Asian Pac J Cancer Prev 2015;16:2939-46.

11. El-Shemy HA, Aboul-Soud MA, Nassr-Allah AA, Aboul-Enein KM, Kabash A, Yagi A, et al. Antitumor properties and modulation of antioxidant enzymes’ activity by Aloe vera leaf active principles isolated via supercritical carbon dioxide extraction. Curr Med Chem 2010;17:129-38.

12. Yang X, Eilerman RG. Pungent principal of Alpinia galangal (L.) swartz and its applications. J Agric Food Chem 1999;47:1657-62.

13. Haraguchi H, Kuwata Y, Inada K, Shingu K, Miyahara K, Nagao M, et al. Antifungal activity from Alpinia galanga and the competition for incorporation of unsaturated fatty acids in cell growth. Planta Med 1996;62:308-13.

14. Murakami A, Ohura S, Nakamura Y, Koshimizu K, Ohigashi H 1’-acetoxychavicol acetate, a superoxide anion generation inhibitor, potently inhibits tumor promotion by 12-O-tetradecanoylphorbol-13-acetate in ICR mouse skin. Oncology 1996;53:386-91.

15. Ohnishi M, Tanaka T, Makita H, Kawamori T, Mori H, Satoh K, et al. Chemopreventive effect of a xanthine oxidase inhibitor, 1’-acetoxychavicol acetate, on rat oral carcinogenesis. Jpn J Cancer Res 1996;87:349-56.

16. Samarghandian S, Hadjzadeh MA, Afshari JT, Hosseini M. Antiproliferative activity and induction of apoptotic by ethanolic extract of Alpinia galanga rhizhome in human breast carcinoma cell line. BMC Complement Altern Med 2014;14:192.

17. Lee CC, Houghton P. Cytotoxicity of plants from malaysia and thailand used traditionally to treat cancer. J Ethnopharmacol 2005;100:237-43.

18. Murakami A, Koshimizu K, Ohigashi H. Chemoprevention with food phytochemicals: Screening, rodent studies, and action mechanisms. J Med Food 1998;1:29-38.

19. Matsuda H, Morikawa T, Ueda H, Yoshikawa M. Medicinal foodstuffs. XXVII. Saponin constituents of gotu kola (2): Structures of new ursane- and oleanane-type triterpene oligoglycosides, centellasaponins B, C, and D, from Centella asiatica cultivated in sri lanka. Chem Pharm Bull (Tokyo) 2001;49:1368-71.

20. Inamdar PK, Yeole RD, Ghogare AB, De Souza NJ. Determination of biologically active constituents in Centella asiatica. J. Chromatogr 1996;742:127-30.

21. Bonfill M, Mangas S, Cusidó RM, Osuna L, Piñol MT, Palazón J. Identification of triterpenoid compounds of Centella asiatica by thin-layer chromatography and mass spectrometry. Biomed Chromatogr 2006;20:151-3.

22. Babykutty S, Padikkala J, Sathiadevan PP, Vijayakurup V, Azis TK, Srinivas P, et al. Apoptosis induction of Centella asiatica on human breast cancer cells. Afr J Tradit Complement Altern Med 2008;6:9-16.

23. Pittella F, Dutra RC, Junior DD, Lopes MT, Barbosa NR. Antioxidant and cytotoxic activities of Centella asiatica (L) urb. Int J Mol Sci 2009;10:3713-21.

24. Anand T, Mahadeva N, Phani KG, Farhath K. Antioxidant and DNA damage preventive properties of Centella asiatica (L) Urb. Pharmacogn J 2010;2:53-8.

25. Huang YH, Zhang SH, Zhen RX, Xu XD, Zhen YS. Asiaticoside inducing apoptosis of tumor cells and enhancing anti-tumor activity of vincristine. Ai Zheng 2004;23:1599-604.

26. Siripong P, Kongkathip B, Preechanukool K, Picha P, Tunsuwan K, Taylor W. Cytotoxic diterpenoid constituents from Andrographis paniculata Nees leaves. J Sci Soc Thailand 1992;18:187-94.

27. Mishra SK, Sangwan NS, Sangwan RS. Andrographis paniculata (Kalmegh): A review. Pharmacogn Rev 2007;1:283-98.

28. Rajagopal S, Kumar RA, Deevi DS, Satyanarayana C, Rajagopalan R. Andrographolide, a potential cancer therapeutic agent isolated from Andrographis paniculata. J Exp Ther Oncol 2003;3:147-58.

29. Jada SR, Matthews C, Saad MS, Hamzah AS, Lajis N, Stevens M, et al. Benzylidene derivatives of andrographolide inhibit growth of breast and colon cancer cells in vitro by inducing G1 arrest and apoptosis. Br J Pharmacol 2008;155:641-54.

30. Gilkes DM, Semenza GL. Role of hypoxia-inducible factors in breast cancer metastasis. Future Oncol 2013;9:1623-36.

31. Brahimi-Horn MC, Pouysségur J. The hypoxia-inducible factor and tumor progression along the angiogenic pathway. Int Rev Cytol 2005;242:157-213.

32. Li J, Zhang C, Jiang H, Cheng J. Andrographolide inhibits hypoxia-inducible factor-1 through phosphatidylinositol 3-kinase/AKT pathway and suppresses breast cancer growth. Onco Targets Ther 2015;8:427-35.

33. Harjotaruno S, Widyawaruyanti A, Zaini NC. Apoptosis inducing effect of andrographolide on TF-47 human breast cancer cell line. Afr J Tradit Complement Altern Med 2008;4:345-51.

34. Banerjee M, Singh P, Panda D. Curcumin suppresses the dynamic instability of microtubules, activates the mitotic checkpoint and induces apoptosis in mcf-7 cells. FEBS J 2010;277:3437-48.

35. Ramachandran C, You W. Differential sensitivity of human mammary epithelial and breast carcinoma cell lines to curcumin. Breast Cancer Res Treat 1999;54:269-78.

36. Zong H, Wang F, Fan QX, Wang LX. Curcumin inhibits metastatic progression of breast cancer cell through suppression of urokinase-type plasminogen activator by NF-kappa B signaling pathways. Mol Biol Rep 2012;39:4803-8.

37. Sharma K, Pachauri SD, Khandelwal K, Ahmad H, Arya A, Biala P, et al. Anticancer effects of extracts from the fruit of Morinda citrifolia (Noni) in breast cancer cell lines. Drug Res 2015;66:141-7.

38. Palu AK, Chen S, Jensen J. Noni (Morinda citrifolia L.) Fruit juice anti-breast cancer potential: A mechanism involving its aromatase enzyme inhibitory effect. J Med Food Plants 2009;1:55-7.

39. Bashri G, Singh VP, Prasad SM. A Review on nutritional and antioxidant values, and medicinal properties of Trigonella foenum-graecum L. Biochem Pharmacol 2013;2: 118. doi:10.4172/2167-0501.1000118.

40. Srinivasan S, Koduru S, Kumar R, Venguswamy G, Kyprianou N, Damodaran C, et al. Diosgenin targets akt-mediated prosurvival signaling in human breast cancer cells. Int J Cancer 2009;125:961-7.

41. Khoja KK, Shaf G, Hasan TN, Syed NA, Al-Khalifa AS, Al-Assaf AH, et al. Fenugreek, a naturally occurring edible spice, kills MCF-7 human breast cancer cells via an apoptotic pathway. Asian Pac J Cancer Prev 2011;12:3299-304.

42. Shabbeer S, Sobolewski M, Anchoori RK, Kachhap S, Hidalgo M, Jimeno A, et al. Fenugreek: A naturally occurring edible spice as an anticancer agent. Cancer Biol Ther 2009;8:272-8.

43. Alsemari A, Alkhodairy F, Aldakan A, Al-Mohanna M, Bahoush E, Shinwari Z, et al. The selective cytotoxic anti-cancer properties and proteomic analysis of Trigonella foenum-graecum. BMC Complement Altern Med 2014;14:114.

44. Sakarkar D, Deshmukh V. Ethnopharmacological review of traditional medicinal plants for anticancer activity. Int J PharmTech Res 2011;3:298-308.

45. Gurfinkel DM, Chow S, Hurren R, Gronda M, Henderson C, Berube C, et al. Disruption of the endoplasmic reticulum and increases in cytoplasmic calcium are early events in cell death induced by the natural triterpenoid asiatic acid. Apoptosis 2006;11:1463-71.

46. Elkady AI, Abuzinadah OA, Baeshen NA, Rahmy TR. Differential control of growth, apoptotic activity, and gene expression in human breast cancer cells by extracts derived from medicinal herbs Zingiber officinale. J Biomed Biotechnol 2012;2012:614356.

47. Rahman S, Salehin F, Iqbal A. In vitro antioxidant and anticancer activity of young Zingiber officinale against human breast carcinoma cell lines. BMC Complement Altern Med 2011;11:76.

48. Tan ML, Sulaiman SF, Najimuddin N, Samian MR, Muhammad TS. Methanolic extract of Pereskia bleo (Kunth) DC. (Cactaceae) induces apoptosis in breast carcinoma, T47-D cell line. J Ethnopharmacol 2005;96:287-94.

49. Nurestri AS, Norhanom A, Hashim Y, Sim K, Hong S, Lee G, et al. Cytotoxic activity of Pereskia bleo (Cactaceae) against selected human cell lines. Int J Cancer Res 2008;4:20-7.

50. Hassanbaglou B, Hamid AA, Roheeyati AM, Saleh NM, Abdulamir A, Khatib A, et al. Antioxidant activity of different extracts from leaves of Pereskia bleo (Cactaceae). J Med Plant Res 2012;6:2932-7.

51. Er HM, Cheng EH, Radhakrishnan AK. Anti-proliferative and mutagenic activities of aqueous and methanol extracts of leaves from Pereskia bleo (Kunth) DC (Cactaceae). J Ethnopharmacol 2007;113:448-56.

52. Lee HL, Er HM, Radhakrishnan AK. In vitro anti-proliferative and antioxidant activities of stem extracts of Pereskia bleo (Kunth) DC (Cactaceae). Malays J Sci 2009;28:225-39.

53. Mohan S, Abdul AB, Abdelwahab SI, Al-Zubairi AS, Sukari MA, Abdullah R, et al. Typhonium flagelliforme induces apoptosis in CEMss cells via activation of caspase-9, PARP cleavage and cytochrome c release: Its activation coupled with G0/G1 phase cell cycle arrest. J Ethnopharmacol 2010;131:592-600.

54. Mankaran S, Dinesh K, Deepak S. Typhonium falgelliforme: A multipurpose plant. Int Res J Pharm 2013;4:45-8.

55. Alfarabi M, Rosmalawati S, Bintang M, Rofa’ani E. Antiproliferation activity of tuber protein from Typhonium flagelliforme (Lodd.) blume on MCF-7 cell line. Int J Biosci 2015;6:52-60.

56. Punvaningsih E, Widayanti E, Suciati Y. Cytotoxicity assay of Typhonium flagelliforme lodd against breast and cervical cancer cells. Univ Med 2014;33:75-82.

57. Cassileth BR, Deng G. Complementary and alternative therapies for cancer. Oncologist 2004;9:80-9.

58. Dorman T. Herbal medicine and anesthesia. Curr Opin Anesthesiol 2001;14:67-669.

59. Bajwa SJ, Panda A. Alternative medicine and anesthesia: Implications and considerations in daily practice. Ayu 2012;33:475-80.

60. Watson DH, Hones SM. Carcinogenic higher plant metabolites in the human diet in temperate countries: A review. Food Addit Contam 1985;2:25-32.

61. Vázquez B, Avila G, Segura D, Escalante B. Antiinflammatory activity of extracts from Aloe vera gel. J Ethnopharmacol 1996;55:69-75.

62. Lee A, Chui PT, Aun CS, Gin T, Lau AS. Possible interaction between sevoflurane and Aloe vera. Ann Pharmacother 2004;38:1651-4.

63. Rabe C, Musch A, Schirmacher P, Kruis W, Hoffmann R. Acute hepatitis induced by an Aloe vera preparation: A case report. World J Gastroenterol 2005;11:303-4.

64. Hunter D, Frumkin A. Adverse reactions to vitamin E and Aloe vera preparations after dermabrasion and chemical peel. Cutis 1991;47:193-6.

65. Domínguez-Soto L. Photodermatitis to Aloe vera. Int J Dermatol 1992;31:372.

66. Surjushe A, Vasani R, Saple DG. Aloe vera: A short review. Indian J Dermatol 2008;53:163-6.

67. Mokkhasmit M, Swatdimongkol K, Satrawaha P. Study on toxicity of Thai medicinal plants. Bull Dept Med Sci 1971;12:36-65.

68. Gohil KJ, Patel JA, Gajjar AK. Pharmacological review on Centella asiatica: A potential herbal cure-all. Indian J Pharm Sci 2010;72:546-56.

69. Sakina M, Dandiya P. A psycho-neuropharmacological profile of Centella asiatica extract. Fitoterapia 1990;61:291-6.

70. Arora D, Kumar M, Dubey S. Centella asiatica-a review of it’s medicinal uses and pharmacological effects. J Nat Rem 2002;2:143-9.

71. Kligler B, Ulbricht C, Basch E, Kirkwood CD, Abrams TR, Miranda M, et al. Andrographis paniculata for the treatment of upper respiratory infection: A systematic review by the natural standard research collaboration. Explore (NY) 2006;2:25-9.

72. Chainani-Wu N. Safety and anti-inflammatory activity of curcumin: A component of tumeric (Curcuma longa). J Altern Complement Med 2003;9:161-8.

73. Shankar TB, Shantha N, Ramesh H, Murthy IA, Murthy VS. Toxicity studies on turmeric (Curcuma longa): Acute toxicity studies in rats, guineapigs and monkeys. Indian J Exp Biol 1980;18:73-5.

74. West BJ, Jensen CJ, Westendorf J, White LD. A safety review of noni fruit juice. J Food Sci 2006;71:R100-6.

75. Brett JW, Chen XS, Jensen CJ. Hepatotoxicity and subchronic toxicity tests of Morinda citrifolia (noni) fruit. J Toxicol Sci 2009;34:581-5.

76. West BJ, White LD, Jensen CJ, Palu AK. A double-blind clinical safety study of noni fruit juice. Pac Health Dialog 2009; 15:21-32.

77. Guh JH, Ko FN, Jong TT, Teng CM. Antiplatelet effect of gingerol isolated from Zingiber officinale. J Pharm Pharmacol 1995;47:329-32.

78. Rao PU, Sesikeran B, Rao PS, Naidu AN, Rao VV, Ramachandran EP. Short term nutritional and safety evaluation of fenugreek. Nutr Res 1996;16:1495-505.

79. Sim KS, Sri Nurestri AM, Sinniah SK, Kim KH, Norhanom AW. Acute oral toxicity of Pereskia bleo and Pereskia grandifolia in mice. Pharmacogn Mag 2010;6:67-70.

80. Nurestri AS, Sim K, Norhanom A. Phytochemical and cytotoxic investigations of Pereskia grandifolia Haw. (Cactaceae) leaves. J Biol Sci 2009;9:488-93.