Two Newsletters on the use of curcumin with chemotherapy:

Part One

DNC NEWS:  Important change in cancer protocols

Subject:  Curcumin should not be used with certain types of chemotherapy

A study has come to my attention which suggests that curcumin, an extract of turmeric, may inhibit the effect of certain chemotherapy drugs. [1] Although the study which suggests this possibility was in vitro (test tube, it is still important to adhere to this information.  Patients undergoing chemotherapy using Adriamycin (Doxorubicin) and or Cytoxan (Cyclophosphamide) should not be taking curcumin.  We have typically recommended either BCQ from Vital Nutrients or AI from Pure Encapsulations during chemotherapy. Both of the products contain curcumin and should be discontinued if you are receiving either of these drugs.

The other primary ingredients in BCQ or AI are still well indicated for use during chemotherapy and radiation therapy. Rather than using these products we will begin recommending quercetin and bromelain taken without curcumin.

The challenge is that the arguments in favor of using curcumin are still good. Curcumin is well indicated for a number of reasons in a wide variety of cancers, including breast cancer and it may seem tempting to many people to still use it. [2, 3, 4]   Nevertheless at this point and until we have further information, I think it wise to discontinue use until finished with chemotherapy. 

At this point I do not want to attempt using it between chemo sessions when the drug has worn off. The half-life information is confusing to me.  Concentrations of cyclophosphamide metabolites reach a maximum in plasma 2 to 3 hours after an IV dose.  However, the elimination half-life of unchanged cyclophosphamide is 3 to 12 hours (most is eliminated in the form of metabolites).  If you make the assumption that at seven half-lives, the drug is no longer pharmacologically active, then that means waiting 21-84 hours before it may be safe to administer curcumin.  Adriamycin is very confusing from a half-life standpoint.  Plasma disappearance follows a triphasic pattern with mean half-lives of approximately 12 minutes, 3.3 hours, and 30 to 40 hours.  So, waiting to administer curcumin between chemo cycles until the drugs are no longer pharmacologically active seems unreasonable.

So the bottom line: no more BCQ or AI during chemotherapy using Adriamycin or Cytoxan. Use quercetin and bromelain instead.  When done with chemotherapy return to using curcumin.  This change in policy will affect a number of you.  Please call the office or email me if you have questions.




References:
1.  Somasundaram S, Edmund NA, Moore DT, Small GW, Shi YY, Orlowski RZ. Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer. Cancer Res. 2002 Jul 1;62(13):3868-75. 
2. Di GH, Li HC, Shen ZZ, Shao ZM. Analysis of anti-proliferation of curcumin on human breast cancer cells and its mechanism Zhonghua Yi Xue Za Zhi. 2003 Oct;83(20):1764-1768
3.  Ramachandran C, Fonseca HB, Jhabvala P, Melnick SJ, Escalon E INHIBITION OF HUMAN TELOMERASE REVERSE TRANSCRITPASE (hHERT) AND TELOMERASE ACTIVITY BY CURCUMIN IN HUMAN MAMMARY EPITHELIAL AND BREAST CARCINOMA CELL LINES. ScientificWorldJournal. 2001 Jan 1;1(1 Suppl 3):109
4. Duvoix A, Morceau F, Delhalle S, Schmitz M, Schnekenburger M, Galteau MM, Dicato M, Diederich M. Induction of apoptosis by curcumin: mediation by glutathione S-transferase P1-1 inhibition.  Biochem Pharmacol. 2003 Oct 15;66(8):1475-83.


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Part two:
Curcumin:  Not a Black and White Case

Subject:  Taking curcumin concurrently with chemotherapy in cancer treatment may either be contraindicated or it may be indicated; the research is contradictory


Although I often wish that certain things in life would be black and white.  Fortunately it isn't and the world is far more interesting in color.  Nevertheless I am interesting time sorting through the research on curcumin and its use in cancer treatment.  There seems little question that curcumin protects against developing cancer. It slows the growth of cancer cells.  It seems well indicated for anyone with cancer to take it.  It is only when the cancer is being treated with chemotherapy that it gets confusing.

I wrote a newsletter recently after reading an article that suggested curcumin inhibited the effect of several chemotherapy drugs in killing breast cancer cells.  As a result I changed my treatment policy and stopped using curcumin during chemotherapy.  This may have been too hasty a decision. At least to make it a rule.  This is one of the situations which we would like to be in black and white, clear cut, right and wrong, but it isn't.
First let me go back to my concerns about curcumin.   Curcumin is a c-Jun NH(2)-terminal kinase (JNK) inhibitor. [1,2] This thing, a c-Jun NH(2)-terminal kinase (JNK)  is also known as a stress-activated protein kinase (SAPK).  Even the abbreviation SAPK is a mouthful but anyway, SAPK activation is necessary for cell death in response to exposure to certain forms of stress (including various chemotherapeutic agents) and defects in SAPK signaling promote cell survival.  In other words curcumin makes it harder for stress or injury to kill a cell.  Generally this is a good thing except when the stress and trauma happen to be chemotherapy which you are giving on purpose to kill cells. The study which started this entire worry showed that in a test tube, breast cancer cells being treated with Adriamycin or Cytoxan were somewhat protected by curcumin.[3]

Keep in mind that all the studies I'm quoting are in vitro, that is test tube, or in this case cell cultures.  These experiments have not been conducted on living animals and certainly not people.  Will animals and will people respond the same way as cells in a test tube?  Sometimes they do and that is why we pay attention to these studies.

While curcumin is a SAPK inhibitor it does a number of other things which may prove very beneficial during chemotherapy.  For example, curcumin lowers NF-kappaB which is believed to be an important factor in drug resistance in cancer cells. At least this is the case with doxorubicin, 5-FU, cisplatin and Paclitaxel. [4]   So curcumin may prevent drug resistance.

There's a study in which curcumin down regulates NF-KappaB in multiple myeloma cells. By doing this, curcumin made these cancer cells more sensitive to the chemotherapy drugs Vincristine and melphalan.[5]  Another study also showed curcumin reduced drug resistance to Vincristine. [6]

Still another study looked at curcumin and NF-KappaB in prostate cancer. Curcumin increased the effect doxorubicin, 5-FU and Paclitaxel in a dose dependent manner. Pretreatment of prostate cancer cells with curcumin produced a synergistic benefit in killing the cancer cells for all chemotherapeutic agents. [7]

Two other studies found that curcumin significantly reduced drug resistance to cisplatin. One study looked at rats with fibrosarcoma. Not only was drug resistance reduced, but also elevated liver enzymes normalized. [8] In the other, drug resistance in ovarian cancer cells was reduced chemo and curcumin were given together. Curcumin was found to reduce IL-6, which was found to be another mechanism of action for its chemo-enhancing effects.[9] In yet another study, cancer cells resistant to doxorubicin were sensitized to the drug after treatment with curcumin. [10]


What's the bottom line?  At this point there isn't one.  All we have is a wiggly line of dots. The studies are in vitro not in vivo.  How all these different factors will balance out in living systems is beyond prediction.
At this point based on the research I would still suggest stopping curcumin when treating breast cancer with Adriamycin (Doxorubicin) and or Cytoxan (Cyclophosphamide).  I would still encourage its use with prostate, ovarian and maybe other cancers.  I would also encourage its use with Cisplatin, 5-FU, Vincristine and Paclitaxel because it may enhance their effect.  Curcumin may be best used to sensitize cancer cells before chemo is begun rather than after. 

I think the take home message from these newsletters regarding curcumin's use is that the practice of naturopathic medicine is not static.  Our guiding principles and philosophy of practice do not change.  At the same time we do our best to stay in touch with the latest developments in scientific research.  In the treatment of cancer especially the state of knowledge and the standard of care are constantly evolving.  As much as I would like to have a set of black and white protocols to give my patients, there is not such thing.  They are constantly changing based on new research and ongoing clinical experience. 



references:
 1 Am J Physiol Heart Circ Physiol. 2000Sep;279(3):H901-7
 2 Am J Physiol Renal Physiol. 2000 Nov;279(5):F954-9
 3  Somasundaram S, Edmund NA, Moore DT, Small GW, Shi YY, Orlowski RZ. Dietary curcumin inhibits chemotherapy-induced apoptosis in models of human breast cancer. Cancer Res. 2002 Jul 1;62(13):3868-75. 
 4 Biochem Pharmacol. 2002 May 1;63(9):1709-16 Basal levels and patterns of anticancer drug-induced activation of nuclear factor-kappaB (NF-kappaB), and its attenuation by tamoxifen, dexamethasone, and curcumin in carcinoma cells. Chuang SE, Yeh PY, Lu YS, Lai GM, Liao CM, Gao M, Cheng AL.
   5 Blood. 2003 Feb 1;101(3):1053-62. Epub 2002 Sep 05 
Curcumin (diferuloylmethane) down-regulates the constitutive activation of nuclear factor-kappa B and IkappaBalpha kinase in human multiple myeloma cells, leading to suppression of proliferation and induction of apoptosis. Bharti AC, Donato N, Singh S, Aggarwal BB.
  6 Zhong Yao Cai. 2001 Sep;24(9):655-7.  [Study on active constituents of traditional Chinese medicine reversing multidrug resistance of tumor cells in vitro] [Article in Chinese] Zhang H, Yang L, Liu S, Ren L.
  7 Prostate. 2002 May 15;51(3):211-8 Curcumin enhances cytotoxicity of chemotherapeutic agents in prostate cancer cells by inducing p21(WAF1/CIP1) and C/EBPbeta expressions and suppressing NF-kappaB activation. Hour TC, Chen J, Huang CY, Guan JY, Lu SH, Pu YS.
 8 Pharmacol Res. 1999 Mar;39(3):175-9. 
Dietary curcumin with cisplatin administration modulates tumour marker indices in experimental fibrosarcoma. Navis I, Sriganth P, Premalatha B.
  9 J Cell Physiol. 2003 Jan;194(1):63-70  Inhibition of growth and sensitization to cisplatin-mediated killing of ovarian cancer cells by polyphenolic chemopreventive agents. Chan MM, Fong D, Soprano KJ, Holmes WF, Heverling H.
  10 Int J Cancer. 2001 Jun 15;92(6):777-83.   Role of glutathione S-transferase P1, P-glycoprotein and multidrug resistance-associated protein 1 in acquired doxorubicin resistance. Harbottle A, Daly AK, Atherton K, Campbell FC.


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