Well..at least you are appreciative
I know this says panc cancer but..probably applies to BC (ask the doc):
In the last year or so papers have appeared informing us of
natural agents that potentially increase the effect of Gemcitabine against pancreatic cancer and which we should consider using in these patients. They include:
a. Thymoquione extracts of black cumin seed, Nigella sativa
b. Curcumin, an extract of the spice turmeric, Curcuma longa
c. Genestein, an extract of the soybean plant, Glycine max.
d. Resveratrol, and extract of grape skins, Vitis vinifera
e. Epigallocatechin gallate, the extract from green tea, Camellia sinensis
f. Gamma linolenic acid (GLA) from evening primrose oil and other seeds
g. Diindolymethane (DIM) and Sulforaphane from cruciferous vegetables of the Brassicaceae family
h. Apogossypolone an analogue of gossypol, an extract of the cotton plant, Gossypium malvaceae
Nigella sativa:
In vitro studies revealed that preexposure of cells with thymoquinone (25 mumol/L) for 48 h followed by gemcitabine or oxaliplatin resulted in 60% to 80% growth inhibition compared with 15% to 25% when gemcitabine or oxaliplatin was used alone. [6] Black cumin seeds have a very long history of medical use in the Muslim world. The Koran reports that the Prophet Mohammed extolled the virtues of these seeds.
[more info on Nigella:
http://denvernaturopathic.com/Nigella.htm ]
Genestein:
Recent publications have reminded us of the potential of soy bean rich diets. A Last March a study published in Cancer Research told us that this compound almost completely prevented the spread of human prostate cancer in mice. The study used amounts of genistein that were no higher than what a human would eat in a soybean-rich diet.
Investigators from Northwestern University found that genistein decreased metastasis of prostate cancer to the lungs by 96 percent compared with mice that did not eat the compound in their chow - making the study the first to demonstrate genistein can stop prostate cancer metastasis in a living organism.
A 2005 suggests that combining genistein with Gemcitabine might increase benefit in treating pancreatic cancer. The researchers reported that, “…studies were done to measure growth inhibition and degree of apoptotic cell death induced by either genistein alone, gemcitabine alone, or genistein followed by gemcitabine. Our results show that pretreatment of cells with genistein for 24 hours followed by gemcitabine resulted in 60% to 80% growth inhibition compared with 25% to 30% when gemcitabine was used alone.” [7]
Curcumin:
The concentrated extract of turmeric root is well enough known for its anticancer effect that there is no need to elaborate on it here. A 2007 study from MD Anderson tells us that we must include curcumin on our list of agents that might potentiate the effect of Gemcitabine. The title alone should suffice: “Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products.” [8]
Resveratrol:
One has to hand it to those MD Anderson researchers. They are good at summing up an entire study in the title. The International Journal of Cancer published another paper from this same group from MD Anderson last month, November 2009. It is titled, “Resveratrol, a multi-targeted agent, can enhance antitumor activity of gemcitabine in vitro and in orthotopic mouse model of human pancreatic cancer.” Though that says it all, let’s add one more line from the abstract: “Resveratrol inhibited the proliferation of four different human PaCa cell lines, synergized the apoptotic effects of gemcitabine, inhibited the constitutive activation of NF-kappaB and expressions of bcl-2, bcl-xL, COX-2, cyclin D1, MMP-9 and VEGF.” [9] When translated, this means you should probably give resveratrol to patients with pancreatic cancer.
Green tea
Researchers from Texas A&M in a May 2009 publication, wrote that, “Epigallocatechin-gallate (EGCG)…. sensitized cells to apoptosis induced by gemcitabine (GEM), mitomycin C or 5-fluorouracil…” [10] This work did not involve pancreatic cancer; they were testing green tea’s effect on cholangiocarcinoma, a cancer of the bile ducts. Though probably reasonable to assume the same effect will be seen in pancreatic cancer, it does not appear to have been reported at the time of this review.
Gamma-linolenic acid:
This is the omega-6 fatty acid found in a number of vegetable sources, most notably Evening primrose oil, borage seed oil and hemp seed oil. It is also found in spirulina. Borage seed oil has the highest concentration of GLA. A 2003 report in Pancreatology tells us that, “GLA has a synergistic effect with gemcitabine at concentrations that correspond to in vivo therapeutic doses.” [11]
Cruciferous vegetables:
Diindolymethane (DIM) is a chemical readily available from cruciferous vegetables. A May 2009 paper tells us, “DIM pretreatment of pancreatic cancer cells led to a significantly increased apoptosis (P < 0.01) with suboptimal concentrations of chemotherapeutic agents (cisplatin, gemcitabine and oxaliplatin) compared with monotherapy.” [12] A June 2008 paper tells us that DIM also enhances the effect of Tarceva, another drug used to treat pancreatic cancer. [13]
A July 2009 paper suggests that sulforaphane, another chemical isolated from cruciferous vegetables, especially broccoli, may also be useful. This study looked at, “highly treatment-resistant tumour-initiating cells (TICs) [that] play a central role in the pathogenesis of pancreatic cancer.”
“Sulforaphane prevented NF-kappaB binding, downregulated apoptosis inhibitors and induced apoptosis,” in these TICs more effectively than Gemcitabine or other cancer preventing agents. “…sulforaphane strongly blocked tumour growth and angiogenesis, while combination with TRAIL had an additive effect without obvious cytotoxicity in normal cells…” [14] It would appear both of these phytonutrients from broccoli have arguments that support their use.
Gossypol:
Gossypol is isolated from cotton seeds and is the only one of these suggested supplements that we may have any hesitation to use. Gossypol has pro-apoptotic properties, probably due to the regulation of the Bax and Bcl2. [15] A July 2009 paper suggests gossypol might be useful in treating B-cell lymphomas. [16] A November 2009 study suggests using gossypol in combination with Xeloda in treating drug resistant prostate cancer. [17]
The study of interest though for our discussion is an October 2009 paper that says it may potentiate the effect of Gemcitabine against pancreatic cancer. The researchers reported that when their synthetic analog of gossypol, “…was combined with gemcitabine, increased cytotoxicity and apoptosis was evident.” [18]
Though this is promising, there is reason to be hesitant. This analog used by the researchers is not readily available. Gossypol itself has the potential to cause adverse effects. Chronic ingestion can lead to fertility disorders in men leading to interest in using it as a male contraceptive agent. [19] One might question whether potential infertility is a significant contraindication for someone with pancreatic cancer? Still, we have not routinely used gossypol with our patients at this time.
Pancreatic cancer is lousy. The common treatments, usually Gemcitabine either alone or more frequently in combination with other drugs, provides only limited benefit. Researchers are looking to combine other chemotherapy drugs with Gemcitabine in the hope of getting some increase in benefit. To date these increases have been minimal. There is published data on a growing number of natural substances that may increase benefit. Most are already in widespread use with cancer patients and show little potential for side effects or adverse reactions. Given the desperate nature of this disease, it seems reasonable to consider using them in conjunction with chemotherapy to enhance the benefits of drug treatment.
References:
[1] Burris HA, Moore MJ, Andersen J, et al: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 15:2403-2413, 1997.
[2] Moore MJ, Goldstein D, Hamm J, et al: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the national cancer institute of Canada clinical trials group. J Clin Oncol 25:1960-1966, 2007.
[3] Cunningham, D, Chau I, Stocken D, et al: Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer (abstract PS11). Eur J Cancer 3:4, 2005.
[4] Herrmann R, Bodoky G, Ruhstaller T, et al: Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: A randomized, multicenter, phase III trial of the Swiss group for clinical cancer research and the central European cooperative oncology group. J Clin Oncol 25:2212-2217, 2007.
[5] CONKO-001: Final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine versus observation in patients with resected pancreatic cancer (PC).
2008 ASCO Annual Meeting Abstract No: LBA4504
[6] Banerjee S, Kaseb AO, Wang Z, Kong D, Mohammad M, Padhye S, et al. Antitumor activity of gemcitabine and oxaliplatin is augmented by thymoquinone in pancreatic cancer. Cancer Res. 2009 Jul 1;69(13):5575-83. Epub 2009 Jun 23.
[7] Banerjee S, Zhang Y, Ali S, Bhuiyan M, Wang Z, Chiao PJ, et al. Molecular evidence for increased antitumor activity of gemcitabine by genistein in vitro and in vivo using an orthotopic model of pancreatic cancer. Cancer Res. 2005 Oct 1;65(19):9064-72.
[8] Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P. Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Cancer Res. 2007 Apr 15;67(8):3853-61.
[9] Harikumar KB, Kunnumakkara AB, Sethi G, Diagaradjane P, Anand P, Pandey MK, et al. Resveratrol, a multi-targeted agent, can enhance antitumor activity of gemcitabine in vitro and in orthotopic mouse model of human pancreatic cancer. Int J Cancer. 2009 Nov 11. [Epub ahead of print]
[10] Lang M, Henson R, Braconi C, Patel T. Epigallocatechin-gallate modulates chemotherapy-induced apoptosis in human cholangiocarcinoma cells. Liver Int. 2009 May;29(5):670-7. Epub 2009 Feb 17.
[11] Whitehouse PA, Cooper AJ, Johnson CD. Synergistic activity of gamma-linolenic acid and cytotoxic drugs against pancreatic adenocarcinoma cell lines. Pancreatology. 2003;3(5):367-73; discussion 373-4.
[12] Banerjee S, Wang Z, Kong D, Sarkar FH. 3,3'-Diindolylmethane enhances chemosensitivity of multiple chemotherapeutic agents in pancreatic cancer. Cancer Res. 2009 Jul 1;69(13):5592-600. Epub 2009 Jun 16.
[13] Ali S, Banerjee S, Ahmad A, El-Rayes BF, Philip PA, Sarkar FH. Apoptosis-inducing effect of erlotinib is potentiated by 3,3'-diindolylmethane in vitro and in vivo using an orthotopic model of pancreatic cancer. Mol Cancer Ther. 2008 Jun;7(6):1708-19.
[14] Kallifatidis G, Rausch V, Baumann B, Apel A, Beckermann BM, Groth A, et al. Sulforaphane targets pancreatic tumour-initiating cells by NF-kappaB-induced antiapoptotic signalling. Gut. 2009 Jul;58(7):949-63. Epub 2008 Oct 1.
[15] Wei J, Kitada S, Rega MF, Emdadi A, Yuan H, Cellitti J, et al. Apogossypol derivatives as antagonists of antiapoptotic Bcl-2 family proteins. Mol Cancer Ther. 2009 Apr;8(4):904-13.
[15] Wei J, Kitada S, Rega MF, Stebbins JL, Zhai D, Cellitti J, Yuan H, Emdadi A, Dahl R, Zhang Z, Yang L, Reed JC, Pellecchia M. Apogossypol derivatives as pan-active inhibitors of antiapoptotic B-cell lymphoma/leukemia-2 (Bcl-2) family proteins. J Med Chem. 2009 Jul 23;52(14):4511-23.
[16] Sanli UA, Gorumlu G, Erten C, Gul MK, Cengiz E, Kucukzeybek Y, Karaca B, Atmaca H, Uzunoglu S, Karabulut B, Uslu R. Targeting apoptosis in the hormone- and drug-resistant prostate cancer cell line, DU-145, by gossypol/zoledronic acid combination. Cell Biol Int. 2009 Nov;33(11):1165-72. Epub 2009 Aug 28.
[17] Banerjee S, Choi M, Aboukameel A, Wang Z, Mohammad M, Chen J, Yang D, Sarkar FH, Mohammad RM. Preclinical Studies of Apogossypolone, a Novel Pan Inhibitor of Bcl-2 and Mcl-1, Synergistically Potentiates Cytotoxic Effect of Gemcitabine in Pancreatic Cancer Cells. Pancreas. 2009 Oct 8. [Epub ahead of print]
[18] ] Cao J, Fei R, Zhao Y, Chen H, Jin W, Chen S. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. [Effect of low dose gossypol treatment on male sperm nuclear basic protein][Article in Chinese] 2000 Jun;22(3):220-2.
Re: Gemzar
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