DNC News

 

Overcoming Multi-Drug Resistance in Cancer Therapy

 

Subject: A review of natural substances that reverse Multi-Drug Resistance in Chemotherapy.

 

 

If chemotherapy worked reliably we might say that it was uncomfortable but, worthwhile. The problem is often it doesn't work; cancer cells become immune to chemo. The patient suffers from the chemo but the cancer is untouched.

 

This phenomenon is called drug resistance and many cancers quickly become resistant to many drugs earning the title, Multi-Drug Resistance or MDR for short. Chemo treatments trigger cancer cells to take evasive action. They build fast acting pumping stations which round up the drugs and pump them out through the cell membranes, lowering the concentration and effect of the chemotherapy within the cancer cells. Normal healthy cells do not react this way and so continue being hit by the chemotherapy. Researchers tell us that this pumping action is done by a specific protein, a P-glycoprotein (Pgp) which the cells start to make in heaps. The more P-glycoprotein a cancer cell makes the less it is affected by Doxorubicin, Vincristine, and Taxol. Another protein acts in a similar manner, suitably named, Multidrug Resistance Protein (MRP), but most research is still looking at Pgp.  Researchers are seeking ways to stop the Pgp from pumping chemo drugs out of the cancer cells so the drugs will continue to work. [1] [2] [3] [4]

 

Quite a few substances have been found which have an inhibitory effect on the P-glycoprotein and reverse Multi Drug Resistance. The drug Verapamil works and is often used as a control in comparing the effect of other substances. Searching the literature I recently collected several dozen pages of abstracts reviewing research on natural agents which also inhibit Pgp and MDR.

There is good data on the chemicals found in green tea; ECGC, Theanine, caffeine and xanthines. You may recall that green tea has other anti-tumor properties useful in cancer therapy but we aren't talking about those now. Green tea stops P-glycoprotein from protecting cancer cells from chemo. The advantage of green tea in is its low toxicity. [5] Because green tea stops or slows the Pgp pumps, it increases the chemo agent within cancer cells but not in healthy cells. [6] One specific green tea extract called Theanine was studied separately. Theanine is something of a hot seller in the herbal market these days; it is used to reduce anxiety and mellow anxious people out. That it acts as a specific to maintain chemo sensitivity is not part of the normal sales pitch. Few cancer patients are happy are about their situation, some are quite anxious. I know of no prescription anti-anxiety medications that can claim as Theanine does, that they boost the effect of chemotherapy. [7]

  In an experiment with mice given drug resistant ovarian cancer, Theanine significantly enhanced the inhibitory effect of doxorubicin on tumor growth and increased the drug's concentration in the tumor, compared to the control group which was given doxorubcin alone. Oral doses of Theanine or green tea enhanced the antitumor activity of doxorubicin. The combination of Theanine with chemo suppressed the spread of ovarian cancer to the liver. Even though Theanine increased the concentration of the chemo drug in cancer cells no increase was observed in normal tissues, such as liver and heart. The Theanine normalized levels of lipid peroxide (LPO) and reduced levels of glutathione peroxidase activity which are both indicators of the collateral damage normally caused by doxorubicin. [8]

  Another study looking at mice with ovarian cancer used a cancer cell line that was so drug resistant that treating the mice with doxorubicin alone had no effect on the tumors. Adding green tea extracts along with the chemo reduced the tumor size by 62%. Not surprising since the concentration of the chemo drug was increased within the cancer cells by 2.7 times. [9] Another study looked at mice given Ehrlich ascites tumors and green tea increased the inhibitory effect of doxorubicin by 2.5 times. [10]

 

Green tea is not the only herbal extract shown to have potential in reversing multi-drug resistance. Another common herb to have effect is ginseng. [11] [12] Like green tea, ginseng has other effects which cancer patients may benefit from. Ginseng acts as a mild stimulant reducing fatigue and improving mood. Both are common complaints during cancer treatment. Quite a number of other plant extracts have also been researched.

 

Curcumin, the extract from turmeric, fits into this category of inhibiting P-glycoprotein and reversing Multi Drug Resistance. [13] [14] So does cinchonine a chemical extract from the same plant from which we derive Quinine. [15] One might argue for the benefit of Tonic Water which is flavored with Quinine in cancer treatment. There are also a number of plants traditionally used in Chinese and Ayurvedic Medicine for the treatment of cancer which are showing similar effects: persimmon peels [16] , Euphorbia, [17] [18] [19] [20] Salvia miltiorrhizae [21] , Amooranin [22] , Radix peucedani [23] , and other combinations of plants traditionally used in Chinese medicine. [24] [25] Most of these plants are still rarely used to my knowledge in Western herbal medicine, but trust me we'll be watching for them as they come into use.

Progesterone is something you are more likely to recognize. Women frequently use this steroid hormone to treat PMS, miscarriage and menopausal complaints. It appears useful, especially when used with Vincristine. Acting like the other P-glycoprotein inhibitors, progesterone increases concentrations of the chemo drugs within the cancer cells but not in healthy cells. [26]

Vitamin C [27] [28] and Vitamin K-3 [29] [30] have been tested individually and reverse multi-drug resistance. Our regular readers will remember that we are strong advocates of using the two together in a 100/1 ratio because this causes a specific form of cell death called autoschizis. Selenium also can partially reverse MDR. [31]

The pituitary hormone melatonin while decreasing side effect damage of chemo at the same time appears to make cancer cells more sensitive also by reducing MDR. [32]

There is an interesting bit of dietary research. Diets low in the amino acids tyrosine and phenylalanine makes cancer cells more sensitive to chemotherapy. [33] Meat, dairy, eggs as well as almonds, avocados and bananas are good food sources of Tyrosine. Phenylalanine is found in most protein rich foods but good sources are found in dairy products, almonds, avocados, lima beans, peanuts and seeds. Avoiding these foods is probably not practical. It makes sense not to go out of one's way to consume either of these amino acids in supplements. NutraSweet or aspartame artificial sweeteners should thus be avoided because of their phenylalanine content.

 

Several studies have also looked at the effect of both sweet red and green peppers and found them useful. They were using extracts of the peppers but you have to think that eating extra peppers certainly won't hurt the cause. [34] [35]

 

These concepts in chemosensitivity are new. Most of the references I've mentioned are fairly recent, in the last five or so years. We should expect to see continuing research in this area and hopefully widespread application of these concepts in cancer treatment.

References:

[1] Clin Cancer Res. 1998 Feb;4(2):389-98. Levels of multidrug resistance (MDR1) P-glycoprotein expression by human breast cancer correlate with in vitro resistance to taxol and doxorubicin.. Mechetner E, Kyshtoobayeva A, Zonis S, Kim H, Stroup R, Garcia R, Parker RJ, Fruehauf JP.

[2] Int J Clin Pharmacol Ther. 2000 Apr;38(4):187-95. Diverse effects of P-glycoprotein inhibitory agents on human leukemia cells expressing the multidrug resistance protein (MRP). Lehne G, Morkrid L, den Boer M, Rugstad HE.

[3] J Nat Prod. 1996 Jan;59(1):35-40. Bicinchoninic acid protein assay in the determination of adriamycin cytotoxicity modulated by the MDR glycoprotein.. Hall AM, Croy V, Chan T, Ruff D, Kuczek T, Chang C.

[4] Hum Cell. 1999 Sep;12(3):95-102. [Mechanisms for resistance to anticancer agents and the reversal of the resistance] [Article in Japanese]. Akiyama S, Chen ZS, Kitazono M, Sumizawa T, Furukawa T, Aikou T.

[5] Nucl Med Biol. 2001 Aug;28(6):735-40. Study of tea polyphenol as a reversal agent for carcinoma cell lines' multidrug resistance (study of TP as a MDR reversal agent).. Zhu A, Wang X, Guo Z.

[6] Toxicol Lett. 2000 Apr 3;114(1-3):155-62. Efficacies of tea components on doxorubicin induced antitumor activity and reversal of multidrug resistance.

Sadzuka Y, Sugiyama T, Sonobe T.

[7] Biochim Biophys Acta. 2003 Dec 5;1653(2):47-59. Theanine and glutamate transporter inhibitors enhance the antitumor efficacy of chemotherapeutic agents. Sugiyama T, Sadzuka Y.

[8] Biochim Biophys Acta. 2003 Dec 5;1653(2):47-59. Theanine and glutamate transporter inhibitors enhance the antitumor efficacy of chemotherapeutic agents. Sugiyama T, Sadzuka Y.

[9] Cancer Lett. 1998 Nov 13;133(1):19-26. Enhancing effects of green tea components on the antitumor activity of adriamycin against M5076 ovarian sarcoma. Sugiyama T, Sadzuka Y.

[10] Clin Cancer Res. 1998 Jan;4(1):153-6. Modulation of cancer chemotherapy by green tea. Sadzuka Y, Sugiyama T, Hirota S .

[11] Biochem Pharmacol. 2003 Jan 1;65(1):75-82. Reversal of P-glycoprotein-mediated multidrug resistance by ginsenoside Rg(3)..Kim SW, Kwon HY, Chi DW, Shim JH, Park JD, Lee YH, Pyo S, Rhee DK.

[12] Planta Med. 2003 Mar;69(3):235-40. Reversal of P-glycoprotein-mediated multidrug resistance by protopanaxatriol ginsenosides from Korean red ginseng.Choi CH, Kang G, Min YD.

[13] Biochem Pharmacol. 2002 Aug 15;64(4):573-82 Modulation of P-glycoprotein expression and function by curcumin in multidrug-resistant human KB cells. Anuchapreeda S, Leechanachai P, Smith MM, Ambudkar SV, Limtrakul PN.

[14] BMC Cancer. 2004 Apr 17;4(1):13 Modulation of human multidrug-resistance MDR-1 gene by natural curcuminoids. Limtrakul P, Anuchapreeda S, Buddhasukh D.

[15] J Pharm Pharmacol. 2001 Jul;53(7):1029-39. Apoptosis induced by doxorubicin and cinchonine in P388 multidrug-resistant cells. Furusawa S, Nakano S, Wu J, Sakaguchi S, Takayanagi M, Sasaki KI, Satoh S.

[16] Phytother Res. 2003 May;17(5):495-500 Biological activity of persimmon (Diospyros kaki) peel extracts.

Kawase M, Motohashi N, Satoh K, Sakagami H, Nakashima H, Tani S, Shirataki Y, Kurihara T, Spengler G, Wolfard K, Molnar J.

[17] Planta Med. 2004 Jan;70(1):81-4. Pubescenes, jatrophane diterpenes, from Euphorbia pubescens, with multidrug resistance reversing activity on mouse lymphoma cells. Valente C, Ferreira MJ, Abreu PM, Gyemant N, Ugocsai K, Hohmann J, Molnar J.

[18] Planta Med. 2004 Jan;70(1):45-9 Rearranged jatrophane-type diterpenes from euphorbia species. Evaluation of their effects on the reversal of multidrug resistance. Madureira AM, Ferreira MJ, Gyemant N, Ugocsai K, Ascenso JR, Abreu PM, Hohmann J, Molnar J.

[19] J Med Chem. 2004 Feb 12;47(4):988-92. Jatrophane diterpenes as modulators of multidrug resistance. Advances of structure-activity relationships and discovery of the potent lead pepluanin A. Corea G, Fattorusso E, Lanzotti V, Motti R, Simon PN, Dumontet C, Di Pietro A.

[20] J Med Chem. 2002 Jun 6;45(12):2425-31 Discovery and biological evaluation of a new family of potent modulators of multidrug resistance: reversal of multidrug resistance of mouse lymphoma cells by new natural jatrophane diterpenoids isolated from Euphorbia species. Hohmann J, Molnar J, Redei D, Evanics F, Forgo P, Kalman A, Argay G, Szabo P.

[21] Mol Pharmacol. 2004 Jan;65(1):77-84. Salvinal, a novel microtubule inhibitor isolated from Salvia miltiorrhizae Bunge (Danshen), with antimitotic activity in multidrug-sensitive and -resistant human tumor cells. Chang JY, Chang CY, Kuo CC, Chen LT, Wein YS, Kuo YH.

[22] Breast Cancer Res Treat. 2003 Aug;80(3):321-30. Novel drug amooranin induces apoptosis through caspase activity in human breast carcinoma cell lines. Rabi T, Ramachandran C, Fonseca HB, Nair RP, Alamo A, Melnick SJ, Escalon E.

[23] Eur J Pharmacol. 2003 Jul 18;473(1):9-17 Reversal of multidrug resistance in cancer cells by pyranocoumarins isolated from Radix Peucedani. Wu JY, Fong WF, Zhang JX, Leung CH, Kwong HL, Yang MS, Li D, Cheung HY.

[24] Blood Cells Mol Dis. 2002 Mar-Apr;28(2):160-8. Activity of drugs from traditional Chinese medicine toward sensitive and MDR1- or MRP1-overexpressing multidrug-resistant human CCRF-CEM leukemia cellsEfferth T, Davey M, Olbrich A, Rucker G, Gebhart E, Davey R.

[25] Anticancer Res. 2001 Jul-Aug;21(4A):2273-80. Screening and discovery of novel MDR modifiers from naturally occurring bisbenzylisoquinoline alkaloids. Fu LW, Deng ZA, Pan QC , Fan W.

[26] Biochemistry. 1996 Apr 16;35(15):4820-7. Steroid treatment, accumulation, and antagonism of P-glycoprotein in multidrug-resistant cells. Barnes KM, Dickstein B, Cutler GB Jr, Fojo T, Bates SE.

[27] In Vivo. 2003 May-Jun;17(3):289-92. Chemosensitizing effect of vitamin C in combination with 5-fluorouracil in vitro.Nagy B, Mucsi I, Molnar J, Varga A, Thurzo L.

[28] Life Sci. 2003 Jul 11;73(8):981-91. Reversal of P-glycoprotein expressed in Escherichia coli leaky mutant by ascorbic acid. El-Masry EM, Abou-Donia MB .

[29] Anticancer Drugs. 1991 Apr;2(2):159-68. ks

Modulation of thiol pools by vitamin K3 and its effect on survival of sensitive and resistant murine tumor cells. Parekh H, Chavan S, Chitnis M.

[30] Cancer Lett. 1992 Jan 10;61(2):147-56. Circumvention of adriamycin resistance: effect of 2-methyl-1,4-naphthoquinone (vitamin K3) on drug cytotoxicity in sensitive and MDR P388 leukemia cells. Parekh HK, Mansuri-Torshizi H, Srivastava TS, Chitnis MP.

[31] Cancer Biother. 1995 Fall;10(3):243-8Selenium (Se) cytotoxicity in drug sensitive and drug resistant murine tumour. Shallom J, Juvekar A, Chitnis M.

[32] J Pineal Res. 2001 Oct;31(3):206-13. Effects of melatonin on doxorubicin cytotoxicity in sensitive and pleiotropically resistant tumor cells. Granzotto M, Rapozzi V, Decorti G, Giraldi T.

[33] Nutr Cancer. 1996;25(1):47-60. Tyrosine and phenylalanine restriction sensitizes adriamycin-resistant P388 leukemia cells to adriamycin. Elstad CA, Thrall BD, Raha G, Meadows GG.

[34] In Vivo. 2001 Sep-Oct;15(5):437-42. Biological activity of a fruit vegetable, "Anastasia green", a species of sweet pepper. Motohashi N, Kurihara T, Wakabayashi H, Yaji M, Mucsi I, Molnar J, Maruyama S, Sakagami H, Nakashima H, Tani S, Shirataki Y, Kawase M.

[35] Phytother Res. 2003 Apr;17(4):348-52. Cytotoxic and multidrug resistance reversal activity of a vegetable, 'Anastasia Red', a variety of sweet pepper. Motohashi N, Wakabayashi H, Kurihara T, Takada Y, Maruyama S, Sakagami H, Nakashima H, Tani S, Shirataki Y, Kawase M, Wolfard K, Molnar J.


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