Feverfew and Multiple Myeloma
Jacob Schor ND FABNO
Studies on parthenolide, an extract from the common herb feverfew, suggest possible benefit for patients with multiple myeloma, enough so that we now consider using it for treating this condition.
We first wrote about feverfew and its possible role in treating cancer about 6 years ago. That newsletter is still posted at: http://denvernaturopathic.com/news/feverfew.html
At that time the theory that cancer tumors were the descendents of cancerous stem cells was just starting to be considered. That feverfew parthenolide could inhibit cancer stem cells was intriguing. Over the last half decade acceptance of the stem cell theory of cancer has become more widespread. Dr. Siddhartha Mukherjee, author of “The Emperor of All Maladies: A Biography of Cancer,” wrote an interesting piece on stem cells for the New York Times that sums up the current understanding. Titled “The Cancer Sleeper Cell,” Mukherjee’s article appeared in the Sunday Magazine section October 29, 2010. It can be read at:
In light of this past history it’s worth looking at the half dozen or so papers suggesting feverfew for multiple myeloma.
The earliest paper that I’ve found on the topic was published July 2006
Cheng et al reported that they had cultured human multiple myeloma (MM) cells and exposed them to various dilutions of parthenolide while measuring growth rates. Exposure to the parthenolide “… significantly inhibited the proliferation and viability of the MM cells time and dose-dependently (all P < 0.01), and significantly induced the cell apoptosis after 48 h in a dose-dependent manner (P < 0.01).” Depending on concentration of parthenolide as many as 40% of the cells underwent apoptosis (cellular suicide). [at 10 micromol/L apoptosis rate was 40.9% +/- 3.1%]
In December of the same year Wang et al reported that parthenolide induced apoptosis in MM cells by increasing reactive oxygen species within the cells and that activity of intracellular catalase is a crucial determinant of their sensitivity to parthenolide.
The next addition to our knowledge was an article by Suvannasankha et al from Indiana University in March 2008. They explored the effects of parthenolide on multiple myeloma cells in the context of the bone marrow microenvironment. They reported that parthenolide inhibited growth of MM cells lines, including drug-resistant cell lines, and primary cells in a dose-dependent manner. Parthenolide canceled out the growth stimulating effects of cytokines interleukin-6 and insulin-like growth factor I.
In addition, parthenolide blocked interleukin-6 secretion from bone marrow stromal cells triggered by the adhesion of MM cells. Parthenolide cytotoxicity is both caspase-dependent and caspase-independent. The parthenolide actually triggers chemical changes within the myeloma cells that make them more sensitive to parthenolide so that over time lower amounts of parthenolide were required to inhibit growth. An additive effect and synergy were observed when parthenolide was combined with dexamethasone and TNF-related apoptosis-inducing ligand, respectively.
A paper by Kong et al published in October 2008 further details the various mechanisms of action rgr parthenolide has on multiple myeloma cells.
It inhibits the angiogenesis (building new blood vessels required to supply cells with oxygen and food) induced by multiple myeloma cells. It also decreases NF-kappaB activity and significantly suppresses the expression of VEGF and IL-6 mRNA and protein. This might in part explain why parthenolide inhibited the angiogenesis induced by MM cells.
The most recent contribution is a June 2011 paper by Gunn et al that looked at the action of both parthenolide and andrographolide. They were able to demonstrate that both products have a “potent” effect against multiple myeloma cancer stem cells and not just against the cancer cells. The later chemical tested andrographolide is a constituent of a tropical plant Andrographis paniculata and probably should be the subject of another newsletter as recent findings suggest that it too may possess desirable action action against a range of tumor types. For example a December 2011 paper suggests it may enhance the effect of chemotherapy against ovarian cancer.
Given our long experience of using feverfew in treating migraine headaches and also the phase I trial that suggests low if any toxicity as mentioned in our earlier article, it seemed reasonable for patients with multiple myeloma to try adding it to their treatment protocol.
Yet as soon as had I come to this conclusion and sent out the above information in a newsletter, I received an email from a woman with multiple myeloma who told me that she had tried taking feverfew a few years ago and that while taking it all of her disease blood markers worsened.
That’s not what one wants to read before breakfast.
During the period that she experimented with feverfew, it seems she was also deficient in vitamin D. This may be important. Give me a few moments to explain.
In the December 2010 issue of Blood, Hassane et al from Weill Cornell Medical College, reported some interesting findings on feverfew parthenolide and acute myeloid leukemia. These researchers had previously reported that parthenolide “… can impair the survival and leukemogenic activity of primary human acute myeloid leukemia (AML) stem cells. However, despite the activity of this agent, PTL also induces cellular protective responses that likely function to reduce its overall cytotoxicity.” In other words, parthenolide while ‘impairing the cancer stem cells, also appeared somewhat protective, reducing overall cytotoxicty.
So Hassane’s group looked for other chemicals that might counter this protective effect and make parthenolide more toxic to the unwanted stem cells.
They found that compounds acting along the phosphatidylinositol 3-kinase 9
(PI3K) and mammalian target of rapamycin (mTOR) pathways enhanced the action of parthenolide and significantly decreased tumor burden. This would suggest that combining parthenolide with drugs that impact these two pathways might increase benefit.
By the way, for those of you who are curious about what “mTOR” means, this is an abbreviation for “mammalian targets of rapamycin. Rapamycin is a drug used in cancer chemotherapy. Before it was understood exactly how the drug worked, this somewhat vague name was applied to the chemical pathways on which the drug acted. The pathways targeted by the drug, in mammals.
Thus Hassane et al’s work suggests that feverfew might be more effective in combination with rapamycin.
We should also pay attention to things that might enhance the effect of rapamycin. Resveratrol appears to do this. In certain types of cancer, reseveratrol inhibits both mTOR and PI-3K pathways.
While we continue to see studies suggesting resveratrol has a favorable action on multiple myeloma, many of us still view its use with caution in multiple myeloma, recalling the SKG clinical trial on treating multiple myeloma with reseveratrol that was canceled due to apparently negative outcomes.
Vitamin D may also impact mTOR pathways. If so, a vitamin D deficiency may have a greater negative impact in combination with feverfew than one might have guessed. Perhaps this may be why my correspondent experienced a negative response to taking feverfew? An older paper (from 2002) tells us that vitamin D in combination with feverfew enhances differentiation of leukemia cells. Differentiation is a favorable sign, the cells appear less cancerous and more ‘normal.’ Perhaps vitamin D deficiency causes an unfavorable response with feveverfew increasing rather than suppressing mTOR pathways?
What else besides resveratrol might have a favorable impact on feverfew action?
Sulforaphane derived from sprouted broccoli may potentially block mTOR pathways, at least it does so in a mouse model of prostate cancer.
Wu et al reported in November 2011 that a curcumin derivative, tetrahydrocurcumin, impacts both the PI-3K and mTOR pathways. A few months earlier in July, Wong et al had announced that curcumin inhibited growth of leiomyosarcoma cells also by inhibiting these same pathways. While both rampamycin and curcumin slowed growth of these cancer cells, at high concentrations, only curcumin triggered apoptosis (cell suicide); rapamycin did not.
Today’s take home lesson is that biology is rarely as simple as we would want. Although feverfew parthenolide would seem to be safe and potentially beneficial in the treatment of multiple myeloma, we should approach parthenolide use with caution. We should test vitamin D levels in the patient prior to instituting treatment with feverfew and raise the levels if low. We should then monitor blood markers with care as feverfew treatment is initiated and suspend use if adverse effects are seen. If a patient is stable on feverfew we might then consider adding sulforaphane and resveratrol.
Chen ZC, Li QB, Shao J, Lü J, You Y, Zhong ZD, Zou P. [Proliferation inhibiting and apoptosis inducing effects of parthenolide on human multiple myeloma cells]. Zhonghua Yi Xue Za Zhi. 2006 Jul 25;86(28):1993-6.
[Article in Chinese]
Apoptosis. 2006 Dec;11(12):2225-35. Parthenolide-induced apoptosis in multiple myeloma cells involves reactive oxygen species generation and cell sensitivity depends on catalase activity. Wang W, Adachi M, Kawamura R, Sakamoto H, Hayashi T, Ishida T, Imai K, Shinomura Y.
Clin Cancer Res. 2008 Mar 15;14(6):1814-22.
Antimyeloma effects of a sesquiterpene lactone parthenolide
Suvannasankha A, Crean CD, Shanmugam R, Farag SS, Abonour R, Boswell HS, Nakshatri H.
J Huazhong Univ Sci Technolog Med Sci. 2008 Oct;28(5):525-30. Epub 2008 Oct 10.
Inhibitory effects of parthenolide on the angiogenesis induced by human multiple myeloma cells and the mechanism.
Kong F, Chen Z, Li Q, Tian X, Zhao J, Yu K, You Y, Zou P.
Anticancer Res. 2011 Dec;31(12):4283-9. Synergism from the combination of oxaliplatin with selected phytochemicals in human ovarian cancer cell lines.Yunos NM, Beale P, Yu JQ, Huq F.
Hassane DC, Sen S, Minhajuddin M, Rossi RM, Corbett CA, Balys M, Wei L, Crooks PA, Guzman ML, Jordan CT. Chemical genomic screening reveals synergism between parthenolide and inhibitors of the PI-3 kinase and mTOR pathways. Blood. 2010 Dec 23;116(26):5983-90. Epub 2010 Oct 1.
He X, Wang Y, Zhu J, Orloff M, Eng C. Resveratrol enhances the anti-tumor activity of the mTOR inhibitor rapamycin in multiple breast cancer cell lines mainly by suppressing rapamycin-induced AKT signaling. Cancer Lett. 2011 Feb 28;301(2):168-76. Epub 2010 Dec 17.
Jiang H, Shang X, Wu H, Gautam SC, Al-Holou S, Li C, Kuo J, Zhang L, Chopp M. Resveratrol downregulates PI3K/Akt/mTOR signaling pathways in human U251 glioma cells. J Exp Ther Oncol. 2009;8(1):25-33.
Free PMC Article
Lisse TS, Hewison M. Vitamin D: a new player in the world of mTOR signaling.
Cell Cycle. 2011 Jun 15;10(12):1888-9. Epub 2011 Jun 15.
Br J Pharmacol. 2002 Mar;135(5):1235-44.
Enhancement of 1 alpha,25-dihydroxyvitamin D(3)-induced differentiation of human leukaemia HL-60 cells into monocytes by parthenolide via inhibition of NF-kappa B activity.
Kang SN, Kim SH, Chung SW, Lee MH, Kim HJ, Kim TS.
Keum YS, Khor TO, Lin W, Shen G, Kwon KH, Barve A, Li W, Kong AN. Pharmacokinetics and pharmacodynamics of broccoli sprouts on the suppression of prostate cancer in transgenic adenocarcinoma of mouse prostate (TRAMP) mice: implication of induction of Nrf2, HO-1 and apoptosis and the suppression of Akt-dependent kinase pathway. Pharm Res. 2009 Oct;26(10):2324-31. Epub 2009 Aug 8.
Wu JC, Lai CS, Badmaev V, Nagabhushanam K, Ho CT, Pan MH. Tetrahydrocurcumin, a major metabolite of curcumin, induced autophagic cell death through coordinative modulation of PI3K/Akt-mTOR and MAPK signaling pathways in human leukemia HL-60 cells. Mol Nutr Food Res. 2011 Nov;55(11):1646-54. doi: 10.1002/mnfr.201100454. Epub 2011 Sep 19.
Wong TF, Takeda T, Li B, Tsuiji K, Kitamura M, Kondo A, Yaegashi N. Curcumin disrupts uterine leiomyosarcoma cells through AKT-mTOR pathway inhibition. Gynecol Oncol. 2011 Jul;122(1):141-8. Epub 2011 Mar 29.