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Advances in Complementary &Alternative Medicine

Indian Medicinal Plants: An Emerging Complementary Adjuvant Therapy for Cancer Treatment

Nidhi Gupta, Raman Kumar, Rehan Khan and Alpana Sharma*

Department of Biochemistry, All India Institute of Medical Sciences, India

*Corresponding author: Alpana Sharma, Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India

Submission: February 01, 2018; Published: February 27, 2018

DOI: 10.31031/ACAM.2018.01.000519

ISSN: 2637-7802
Volume1 Issue4

Abstract

Cancer being one of the distressing diseases requires special consideration with respect to therapeutics. Despite the availability of a number of chemotherapeutic drugs, vast majority of cancer cases relapse which might be due to the development of drug resistance. Moreover, these chemotherapeutics possess severe side effects and are expensive. Taken these drawbacks of chemotherapeutics into account, an emerging role of traditional Indian medicinal system has been studied and evaluated in a variety of tumors ranging from solid tumors to haematological malignancies. Several such medicinal plants such as curcumin, cinnamon, ashwagandha, ginger, long pepper, etc have shown promising anti-tumor effect alone or as adjuvant chemotherapy. Furthermore, the effect of these medicinal plants on drug resistant tumor cells have also been investigated and found that the proteins up regulated while development of drug resistance such as P-glycoprotein have been suppressed by these medicinal plants suggesting their chemo-sensitizing role in treatment of cancer.

Keywords: Cancer; Indian medicinal system; Cinnamon; Curcumin; Ginger; Long pepper; Ashwagandha

Introduction

Cancer is one of the distressing diseases globally affecting a considerable number of people. According to the National Cancer Registry Programme of the India Council of Medical Research (ICMR), more than 1300 Indians die every day due to cancer. The mortality rate due to cancer has been increased by approximately 6% between 2012 and 2014. As per Population Cancer Registry of ICMR, the incidence and mortality of cancer is highest in the North Eastern region of the country [1]. A variety of chemotherapeutic drugs (either cytotoxic or immunomodulatory) are currently employed for the treatment of cancers ranging from solid tumors to haematological malignancies but besides being tremendously expensive, these drugs are associated with serious side effects, morbidity and lack of effectiveness [2,3]. Furthermore, frequent failure in chemotherapy leading to relapse necessitates the identification of efficient, cost-effective treatment regimen with minimal side effects.

The plausible cause of cancer recurrence could be the drug resistance or involvement of multiple pathways for the development and progression of cancer. Therefore, in order to overcome these difficulties, utilisation of traditional system of medicine for the treatment of cancer is the main focus of research. However, some of the widely used anticancer drugs, such as taxol and vinca alkaloids, are obtained from medicinal plants. Thus, this review focuses on certain traditional Indian medicines in context with the improved cancer treatment. Ayurveda and Unani systems, the major traditional forms of medical practice in India, have given many useful leads in developing medications for chronic diseases. Being derived from the natural sources, these chemo-preventive agents are considered pharmacologically safe. The current review, although brief, evaluates the untapped therapeutic potential of these agents in the setting of several molecular targets for the treatment of cancer [4].

Cinnamon

Our lab has previously reported the anti-cancer property of Cinnamon Bark Powder Extract (CBPE or dal-chini), an extract of Ayurvedic-Unani origin in Multiple Myeloma (MM) [5]. CBPE (at IC50: 72μg/ml) has shown cytotoxic as well as cytostatic property against myeloma cells (RPMI8226) as exemplified by increase in sub-G1 phase and decrease in G2/M phase in propidium iodide staining on 48hrs and 72hrs (Figure 1). The effect of cinnamon extract has been investigated on angiogenesis, one of the important hallmarks of cancer. We have observed significant reduction in angiogenic factors such as VEGF, HGF, Angiopoietin-1 and Angiopoietin-2 both at mRNA and protein level as assessed by Q-PCR and western blotting respectively (Figure 2). In addition, the inhibition of cyclooxygenase (COX)-1 and 2 has been observed upon treatment of CBPE in myeloma cells (Figure 3) affirming the anti-myeloma effect of cinnamon extract along with the correlation between angiogenesis and cyclooxygenase which could be studied further for the purpose oftherapeutics in MM. This extract could also be studied in combination with currently used chemotherapeutic drugs (such as lenalidomide or bortezomib) to explore its potential as an alternate and complementary therapy for the malignancy

Other reports have also accounted the concordance findings. 50-70μM cinnamon extract caused growth inhibition of K562 leukemic cells by arresting the cells at the G1 stage and significantly increased the apoptosis rate. Cinnamon extract treatment also showed up regulation of erythroid and myeloid differentiation antigens while down regulation of megakaryocytic differentiation antigens in a dose-dependent manner by investigating antigenic variation of cell surface markers. Hence, Guan et al. [6] suggested the effectiveness of cinnamon extract for the treatment of leukemia. Zhang et al. [7] also reported the suppression of VEGF expression, blood vessel formation, and tumor growth in a human ovarian tumor model in mice treated orally with 0.3mg/g cinnamon extract suspension. These findings support the notion that cinnamon could be effectively used for cancer therapeutics in future with the necessisity of further investigations.

Figure 1: Histograms showing propidium iodide staining of DNA content, with the x-axis reflecting fluorescence intensity and the y-axis the cell number. Flow cytometric determination of cell cycle distribution of RPMI8226 cells following 24h, 48h and 72h of treatment (adapted from Khan et al. [5])

Figure 2: Effect of treatment of CBPE on mRNA (Left Panel) and protein (Right Panel) levels of angiogenic factors in a time dependent manner. (A): Angiopoietin 1 (Ang-1); (B) Angiopoietin 2 (Ang-2); (C): vascular endothelial growth factor (VEGF); (D): hepatocyte growth factor (HGF) (adapted from Khan et al. [5]).

Figure 3: Effect of treatment of CBPE on mRNA (Left Panel) and protein (Right Panel) levels of cyclooxygenase in a time dependent manner. (A): Cyclooxygenase 1 (COX-1); (B) cyclooxygenase 2 (COX-2) (adapted from Khan et al. [5]).

Ginger

The natural herbs contain numerous active components which are likely to target multiple mechanisms would be beneficial for multiple targeted therapies for better treatment of cancer [8]. Ginger (Zingiber officinale), has been used for centuries in Indian traditional medicine system as an anti-inflammatory and antiemetic agent. Ginger or its active chemical component are capable of inducing a potent chemo-sensitizing effect which is the ability of a low concentration of herbal extract or its active component capable of reversing anticancer drug resistance when combined with a particular anticancer drug for which the cancer cells have developed resistance. Some resistant cancer cells such as MES-SA/ Dx-5, doxorubicin-resistant sarcoma cells have shown the overexpression of P-glycoprotein, an efflux pump capable of pumping the active drug from intracellular site to extracellular site and thus decrease drug intracellular concentration. 6-Gingerol (6G), the active principle of ginger root at 20μM concentration has shown the suppression of P-glycoprotein transporter along with the reduction in ROS production in these resistant cells contributing to revert chemo-resistance [9]. Therefore, alone or combination of ginger extract along with chemotherapeutic drugs such as doxorubicin has shown heightened response against breast carcinoma and acute monocytic leukemic cells [10,11].

The effects of ginger extract on tumor xenograft mice model affims its anti-cancer potential. 6-Gingerol, present in the pungent extracts of ginger was given intraperitoneally in HeLa cervical cancer xenograft cells at 2.5mg/kg and 5mg/kg body weight. Treatment with 6G induced significant reduction of tumor volume, tumor weight, proteasome inhibition and p53 accumulation in vivo. The 6G treatment was devoid of any toxic effects as it did not affect body weights, hematological and osteogenic parameters [12]. Thus, cumulatively, these literatures emphasize the therapeutic and chemo-sensitizing effects of ginger in the management and better treatment of variety of cancers.

Curcumin

There are plethoras ofsuch natural medicinal plants tested for the anti-tumor potential in several malignancies. Curcumin (turmeric), an active constituent of Curcuma longa has shown synergistic effect in combination with radiation therapy or chemotherapy in cancers including cervical carcinoma and leukemia [13]. Recently, this Indian spice has shown potent inhibition of growth of non-small cell lung carcinoma cells in vitro via inducing both apoptosis and autophagy suggesting its probable use as candidate therapeutics in human lung carcinoma [14]. Besides the anti-tumor role of curcumin in solid tumors, it has also been reported to suppress the proliferation of chronic myelogenous leukemic cells [15]. Apart from the effect in vitro, several in vivo studies also underscore the antitumor potential of curcumin. Treatment of orthotopic esophageal squamous cell carcinoma bearing mice with 50mg/kg curcumin or 50mg/kg SSC-5 intraperitoneally resulted in an inhibition in tumor growth and invasion [16]. Similar findings were reported for anti-tumor property of curcumin in colon carcinoma and chronic myelogenous leukemic xenograft models in vivo [17,18].

Ashwagandha

Ashwagandha (Withania somnifera) is considered to be one of the important medicinal herb of several traditional systems of medicine, such as Ayurveda, Unani, and Siddha. It had been used for millennia as a Rasayana for its wide ranging health benefits. Yadav et al. [19] reported the anti-cancer property of root, stem and leaves of ashwagandha against human cancer cell lines. Ashwagandha root extract showed dose-dependent inhibition of breast tumor growth and metastatic lung nodule formation with minimal systemic toxicity [20]. The root extract also found to have chemopreventive effect against fore stomach and skin cancer [21]. Apart from reports in solid tumors, there is only a single report of ashwagandha plant extract in hematological malignancy in which DMSO extract obtained from roots of ashwagandha showed cytostatic and cytotoxic activity against human T-lymphoblastoid cell line [22]. In addition, the anti-tumor property of one of the components of ashwagandha, i.e., With aferin A has also been assessed in various cancers [23,24]. Moreover, intraperitoneal injection of 2mg/kg with aferin A significantly reduced the tumor volume in colon carcinoma xenograft model [25]. These results affirm the plausible role of ashwagandha for better cancer therapeutics in future.

Long pepper

Long pepper (Piper longum) has also gained importance in concordance with the anti-tumor potential against a range of tumors. Hang et al. [26] has recently reported the induction of cell death in head and neck squamous cell carcinoma upon treatment with different doses (5μM and 10μM) of piperlongumine, an alkaloid identified in piper longum. Han et al. [27] has also reported the chemosensitizing effect of long pepper by reverting cancer drug resistance. They have observed that co-treatment of Piperine (an alkaloid from long pepper) at 20μM and mitomycin-C (a chemotherapeutic drug) at lower concentration of 0.025μg/ ml resulted in a synergistic suppression of cell proliferation and induction of apoptosis in mitomycin-C resistant cervical cancer cells. They have proposed a novel therapeutic strategy of utilization of piperine to potentiate mitomycin-C induced anti-tumor effect on cervical cancer cells with drug resistance through blocking p-STAT3/p65 and Bcl-2 activation.

Several in vivo studies on tumor xenograft mice model suggested the potential of piper longum or its active constituents in cancer therapeutics. Wang et al. [28] have reported that piperlongumine, a natural product isolated from the fruit of Piper longum, exhibits significant anti-tumor effects against human pancreatic carcinoma in an in vivo xenograft model and this compound enhanced the therapeutic effects of a chemotherapeutic drug, gemcitabine. There are various Indian traditional plants but to summarise, all these plants possess anti-tumor property which should be studied further in tumor xenograft models and clinical trials either alone or in combination with currently used chemotherapeutic drugs in order to identify an efficient, cost effective and less toxic treatment modality for the malignancy. In addition, quality of life of cancer patients could also be improved by the administration of medicinal plants. Therefore, collectively, Indian traditional medicinal plants could prove to be a proficient therapeutic approach as an adjuvant therapy to treat cancer in future.

References

  1. National Cancer Registry Programme (2013) Three-year report ofpopulation based cancer registries: 2009-2011. NCDIR-ICMR, Bangalore, India.
  2. Longley DB, Johnston PG (2005) Molecular mechanisms of drug resistance. J Pathol 205(2): 275-292.
  3. Hamilton G, Rath BA (2014) Short update on cancer chemoresistance. Wien Med Wochenschr 164(21-22): 456-460.
  4. Aggarwal BB, Ichikawa H, Garodia P, Weerasinghe P, Sethi G, et al. (2006) From traditional Ayurvedic medicine to modern medicine: identification of therapeutic targets for suppression of inflammation and cancer. Expert Opin Ther Targets 10(1): 87-118.
  5. Khan R, Sharma M, Kumar L, Husain SA, Sharma A (2016) Cinnamon extract exhibits potent anti-proliferative activity by modulating angiogenesis and cyclooxygenase in myeloma cells. J Herbal Med 6(3): 149-156.
  6. Guan X, Su MC, Zhao RB, Ouyang HM, Dong XD, et al. (2016) Cinnamon effectively inhibits the activity of leukemia stem cells. Genet Mol Res 15(3).
  7. Zhang K, Han ES, Dellinger TH, Lu J, Nam S, et al. (2017) Cinnamon extract reduces VEGF expression via suppressing HIF-1a gene expression and inhibits tumor growth in mice. Mol Carcinog 56(2): 436-446.
  8. Ling CQ, Yue XQ, Ling C (2014) Three advantages of using traditional Chinese medicine to prevent and treat tumor. J Integr Med 12(4): 331335.
  9. Angelini A, Conti P, Ciofani G, Cuccurullo F, Di Ilio C (2013) Modulation of multidrug resistance P-glycoprotein activity by antiemetic compounds in human doxorubicin-resistant sarcoma cells (MES-SA/Dx-5): implications on cancer therapy. J Biol Regul Homeost Agents 27(4): 1029-1037.
  10. Ashmawy NE, Khedr NF, Bahrawy HA, Mansour HE (2017) Ginger extract adjuvant to doxorubicin in mammary carcinoma: study of some molecular mechanisms. Eur J Nutr doi: 10.1007/s00394-017-1382-6.
  11. Omoregie SN, Omoruyi FO, Wright VF, Jones L, Zimba PV (2013) Antiproliferative activities of lesser galangal (Alpinia officinarum Hance Jaml), turmeric (Curcuma longa L.), and ginger (Zingiber officinale Rosc) against acute monocytic leukemia. J Med Food 16(7): 647-655.
  12. Rastogi N, Duggal S, Singh SK, Porwal K, Srivastava VK, et al. (2015) Proteasome inhibition mediates p53 reactivation and anti-cancer activity of 6-gingerol in cervical cancer cells. Oncotarget 6(41): 4331043325.
  13. Baatout S, Derradji H, Jacquet P, Ooms D, Michaux A, et al. (2004) Effect of curcuma on radiation-induced apoptosis in human cancer cells. Int J Oncol 24(2): 321-329.
  14. Liu F, Gao S, Yang Y, Zhao X, Fan Y, et al. (2018) Antitumor activity of curcumin by modulation of apoptosis and autophagy in human lung cancer A549 cells through inhibiting PI3K/Akt/mTOR pathway. Oncol Rep 39(3): 1523-1531.
  15. Fan YJ, Zhou YX, Zhang LR, Lin QF, Gao PZ, et al. (2017) C1206, a novel curcumin derivative, potently inhibits Hsp90 and human chronic myeloid leukemia cells in vitro. Acta Pharmacol Sin.
  16. Tung LN, Song S, Chan KT, Choi MY, Lam HY, et al. (2018) Preclinical study of novel curcumin analogue ssc-5 using orthotopic tumor xenograft model for esophageal squamous cell carcinoma. Cancer Res Treat doi: 10.4143/crt.2017.353.
  17. Zhang P, Lai ZL, Chen HF, Zhang M, Wang A, et al. (2017) Curcumin synergizes with 5-fluorouracil by impairing AMPK/ULK1-dependent autophagy, AKT activity and enhancing apoptosis in colon cancer cells with tumor growth inhibition in xenograft mice. J Exp Clin Cancer Res 36(1): 190.
  18. Larasati YA, Yoneda KN, Nakamae I, Yokoyama T, Meiyanto E, et al. (2018) Curcumin targets multiple enzymes involved in the ROS metabolic pathway to suppress tumor cell growth. Sci Rep 8(1): 2039.
  19. Yadav B, Bajaj A, Saxena AK (2010) In vitro anticancer activity of the root, stem and leaves of withania somnífera against various human cancer cell lines. Ind J Pharma Sci 72(5): 659-663.
  20. Yang Z, Garcia A, Xu S, Powell DR, Vertino PM, et al. (2013) Withania somnifera root extract inhibits mammary cancer metastasis and epithelial to mesenchymal transition. PloS One 8(9): e75069.
  21. Padmavathi B, Rath PC, Rao AR, Singh RP (2005) Roots of withania somnifera inhibit forestomach and skin carcinogenesis in mice. Evid Based Complement Alternat Med 2(1): 99-105.
  22. Turrini E, Calcabrini C, Sestili P, Catanzaro E, Gianni ED, et al. (2016) Withania somnifera induces cytotoxic and cytostatic effects on human T leukemia cells. Toxins 8(5): E147.
  23. Lv TZ, Wang GS (2015) Antiproliferation potential of withaferin A on human osteosarcoma cells via the inhibition of G2/M checkpoint proteins. Exp Ther Med 10(1): 323-329.
  24. Mandal C, Dutta A, Mallick A, Chandra S, Misra L, et al. (2008) Withaferin A induces apoptosis by activating p38 mitogen-activated protein kinase signaling cascade in leukemic cells of lymphoid and myeloid origin through mitochondrial death cascade. Apoptosis 13(12): 1450-1464.
  25. Choi BY, Kim BW (2015) Withaferin-A inhibits colon cancer cell growth by blocking STAT3 transcriptional activity. J Cancer Prev 20(3): 185-192.
  26. Hang W, Yin ZX, Liu G, Zeng Q, Shen XF, et al. (2018) Piperlongumine and p53-reactivator APR-246 selectively induce cell death in HNSCC by targeting GSTP1. Oncogene doi: 10.1038/s41388-017-0110-2.
  27. Han SZ, Liu HX, Yang LQ, Cui LD, Xu Y (2017) Piperine (PP) enhanced mitomycin-C (MMC) therapy of human cervical cancer through suppressing Bcl-2 signaling pathway via inactivating STAT3/NF-KB. Biomed Pharmacother 96: 1403-1410.
  28. Wang Y, Wu X, Zhou Y, Jiang H, Pan S, et al. (2016) Piperlongumine suppresses growth and sensitizes pancreatic tumors to gemcitabine in a xenograft mouse model by modulating the NF-kappa B pathway. Cancer Prev Res (Phila) 9(3): 234-244.

© 2018 Nidhi Gupta, et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and build upon your work non-commercially.



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