Current Research into Botanicals and Cancer

As a follow-up to my post last week, Botanical Medicine: A Symphony in Harmony Against Cancer, I want to present some of the latest research into botanicals and cancer.

Researchers are investigating the potential of botanicals to treat all types of cancers, studying the use of natural compounds to prevent or reverse the process of carcinogenesis. For example, head and neck squamous cell carcinoma (HNSCC) is one of the most fatal cancers. Despite advances in the management of HNSCC, the overall survival for patients has not improved significantly due to advanced stages at diagnosis, high recurrence rate after surgical removal, and second primary tumor development. To develop approaches that can intervene at any stage of cancer development requires understanding of the crosstalk between cancer signaling pathways and networks to retain or enhance chemopreventive activity while reducing known toxic effects. Researchers are discovering that many natural dietary compounds have been identified as multiple molecular targets, effective in the prevention and treatment of cancer.¹

There are hundreds of studies worldwide investigating the potential for botanicals in the prevention and treatment of cancer. The following are a few recent findings:

• In studies using two natural dietary polyphenols, luteolin and epigallocatechin gallate (EGCG) from green tea, researchers found that the combination at low doses (at which single agents induce minimal apoptosis) synergistically increased apoptosis (3-5-fold more than the additive level of apoptosis) in both head and neck and lung cancer cell lines. This combination also significantly inhibited growth of xenografted tumors in nude mice. The in vivo findings also were supported by significant inhibition of Ki-67 expression and increase in TUNEL-positive cells in xenografted tissues.²
• EGCG, the most abundant and researched catechin in green tea extract, is able to enhance the therapeutic efficacy of temozolomide in patients with glioblastoma. EGCG can cross the blood–brain barrier enough to cause chemosensitization in a mouse glioma model. When combined with temozolomide, EGCG reduced the expression levels of glucose-regulated protein 78 in temozolomide-treated animals, which is a key pro-survival component of the endoplasmic reticulum stress response system (EGCG alone did not provide survival benefit). Recently, it was discovered that curcumin combined with temozolomide demonstrated profound synergistic cytotoxic effects in a glioblastoma spheroid model.³
• Studies indicate that when curcumin and EGCG are combined the anti-cancer actions are significantly enhanced. One study found that the combination of curcumin and catechins produces a synergistic colon cancer-preventative effect that is more potent than each of the compounds alone.⁴
• Curcumin and green tea catechins in combination synergistically inhibited the proliferation of HCT 15, HCT 116, as well as Hep G-2 cells efficiently through induction of apoptosis.⁵
• Curcumin combined with EGCG synergistically induced cancer cell apoptosis (cell death) in chronic lymphocytic leukemia B cells.⁶
• The combination of EGCG and curcumin suppresses ER alpha-breast cancer cell growth in vitro and in vivo.⁷
• EGCG potentiated the ability of curcumin to suppress uterine leiomyosarcoma (LMS) cell growth and induce apoptosis. EGCG significantly lowered the concentration of curcumin required to inhibit the AKT-mTOR pathway, reducing cell proliferation and inducing apoptosis in uterine LMS cells. EGCG was able to enhance the intracellular incorporation of curcumin into LMS cells.⁸
• Synergism from sequenced combinations of curcumin and EGCG with cisplatin has been shown to be effective in killing of human ovarian cancer cells.⁹
• Curcumin and EGCG combined with the isothiocyante compound from broccoli spouts (sulforaphane) synergistically suppressed PDGFR/EGFR activation (phosphorylation) in prostate cancer cells.¹⁰
• EGCG potentiated the effect of curcumin in inducing growth inhibition and apoptosis of resistant breast cancer cells; combined with chemotherapy EGCG and curcumin inhibited drug resistance to doxorubicin (DOX).¹¹
• Combining burdock (Arctium lappa) seed compound, arctigenin, with EGCG rich green tea extract and curcumin increased the chemopreventive effect against prostate and breast cancer cells.¹²
• Curcumin and green tea extract inhibit chemotherapy induced pulmonary fibrosis.¹³
• The combination of turmeric and resveratrol, a phenolic compound in grape skin, has recently demonstrated synergistic effects against neuroblastoma cancer.¹⁴

“The mechanisms underlying synergistic therapeutic actions of herbal medicines are:

(1) different agents may regulate either the same or different target in various pathways, and therefore cooperate in an agonistic, synergistic way;

(2) regulate the enzymes and transporters that are involved in hepatic and intestinal metabolism to improve oral drug bioavailability;

(3) overcome the drug resistance mechanisms of microbial and cancer cells; and (4) eliminate the adverse effects and enhance pharmacological potency of agents by “processing” or by drug-drug interaction.”¹⁵

The multi-component nature inherent in medicinal herbs makes them particularly suitable for treating complex diseases; using them in conjunction with multi-drug therapies has the potential to create the most effective outcomes. To identify the bioactive components, one should bear in mind the concept of systems biology, emphasizing a holistic perspective while evaluating the pharmaceutical activity of natural products. The exploration of the synergistic mechanisms of herbal ingredients together with specific drug therapies for cancer offers great potential in the quest for new phytomedicines and drug combinations, with the goal of enhancing health and improving the quality of life for those confronted with cancer.

1. Rahman MA, Amin AR, Shin DM. Chemopreventive potential of natural compounds in head and neck cancer. Nutr Cancer. 2010;62(7):973-87. doi: 10.1080/01635581.2010.509538. Review.
2. Amin AR, Wang D, Zhang H, Peng S, Shin HJ, Brandes JC, Tighiouart M, Khuri FR, Chen ZG, Shin DM. Enhanced anti-tumor activity by the combination of the natural compounds (-)-epigallocatechin-3-gallate and luteolin: potential role of p53. J Biol Chem. 2010 Nov 5;285(45):34557-65. doi: 10.1074/jbc.M110.141135. Epub 2010 Sep 8.
3. Dilnawaz F, Sahoo SK. Enhanced accumulation of curcumin and temozolomide loaded magnetic nanoparticles executes profound cytotoxic effect in glioblastoma spheroid model. Eur J Pharm Biopharm. 2013 Jul 24. doi:pii: S0939-6411(13)00258-0. 10.1016/j.ejpb.2013.07.013.
4. Xu G, Ren G, Xu X, Yuan H, Wang Z, Kang L, Yu W, Tian K. Combination of curcumin and green tea catechins prevents dimethylhydrazine-induced colon carcinogenesis. Food Chem Toxicol. 2009 Oct 24.
5. Manikandan R, Beulaja M, Arulvasu C, Sellamuthu S, Dinesh D, Prabhu D, Babu G, Vaseeharan B, Prabhu NM. Synergistic anticancer activity of curcumin and catechin: an in vitro study using human cancer cell lines. Microsc Res Tech. 2012 Feb;75(2):112-6. doi: 10.1002/jemt.21032. Epub 2011 Jul 21.
6. Ghosh AK, Kay NE, Secreto CR, Shanafelt TD. Curcumin inhibits prosurvival pathways in chronic lymphocytic leukemia B cells and may overcome their stromal protection in combination with EGCG. Clin Cancer Res. 2009 Feb 15;15(4):1250-8.
7. Somers-Edgar TJ, Scandlyn MJ, Stuart EC, Le Nedelec MJ, Valentine SP, Rosengren RJ. The combination of epigallocatechin gallate and curcumin suppresses ER alpha-breast cancer cell growth in vitro and in vivo. Int J Cancer. 2008 May 1;122(9):1966-71.
8. Kondo A, Takeda T, Li B, Tsuiji K, Kitamura M, Wong TF, Yaegashi N. Epigallocatechin-3-gallate potentiates curcumin’s ability to suppress uterine leiomyosarcoma cell growth and induce apoptosis, Int J Clin Oncol. 2012 Feb 15.
9. Yunos NM, Beale P, Yu JQ, Huq F. Synergism from sequenced combinations of curcumin and epigallocatechin-3-gallate with cisplatin in the killing of human ovarian cancer cells. Anticancer Res. 2011 Apr;31(4):1131-40.
10. Farooqi AA, Bhatti S, Rana A, Fayyaz S, Mansoor Q, Javed Z, Riaz AM, Nisar K, Ahsan Qu, Dilawar BA, Asif H, Khanum R, Javeed MK. Shattering the underpinnings of neoplastic architecture in LNCap: synergistic potential of nutraceuticals in dampening PDGFR/EGFR signaling and cellular proliferation; J Exp Ther Oncol. 2011;9(3):201-6.
11. Wang S1, Chen R, Zhong Z, Shi Z, Chen M, Wang Y. Epigallocatechin-3-gallate potentiates the effect of curcumin in inducing growth inhibition and apoptosis of resistant breast cancer cells, Am J Chin Med. 2014;42(5):1279-300. doi: 10.1142/S0192415X14500803.
12. Wang P1, Wang B2, Chung S2, Wu Y3, Henning SM4, Vadgama JV3. Increased chemopreventive effect by combining arctigenin, green tea polyphenol and curcumin in prostate and breast cancer cells, RSC Adv. 2014 Aug 5;4(66):35242-35250.
13. Hamdy MA, El-Maraghy SA, Kortam MA. Modulatory Effects of Curcumin and Green Tea Extract against Experimentally Induced Pulmonary Fibrosis: A Comparison with N-Acetyl Cysteine, J Biochem Mol Toxicol. 2012 Nov 6. doi: 10.1002/jbt.21447.
14. Zhang Y, Vareed SK, Nair MG. Human tumor cell growth inhibition by nontoxic anthocyanidins, the pigments in fruits and vegetables. Life Sciences 2005; 76(13): 1465-1472).
15. Yang Y1, Zhang Z2, Li S2, Ye X3, Li X4, He K5. Synergy effects of herb extracts: pharmacokinetics and pharmacodynamic basis, Fitoterapia. 2014 Jan;92:133-47. doi: 10.1016/j.fitote.2013.10.010. Epub 2013 Oct 28.

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