Curcumin and Interleukin-6 (IL-6)

Curcumin has been shown to have numerous cytotoxic effects on cancer stem cells (CSCs). This is due to its suppression of the release of cytokines, particularly interleukin (IL)-6, IL-8 and IL-1, which stimulate CSCs, and also to its effects at multiple sites along CSC pathways, such as Wnt, Notch, Hedgehog and FAK. In spite of its multiple actions targeting CSCs, curcumin has little toxicity against normal stem cells (NSCs). This may be due to curcumin’s different effects on CSCs and NSCs. The use of cytotoxic therapies remains the standard treatment for patients with metastatic cancer. The efficacy of these treatments is limited, with recurrence common. According to the cancer stem cell paradigm, cancers contain distinct subpopulations of cancer stem/progenitor cells (CSCs) characterized by self-renewal mechanisms and resistance to conventional treatments (1-3). When CSCs are transferred to an immune-deficient mouse, these cells can reconstitute the original cancer in the animal (4-6). Even a small number of stem cells (as few as 100) can be effective in bringing about the transplantation (7). However, tumors depleted of stem cells do not grow as xenografts (8). These CSCs have been shown to be resistant to chemotherapy (9), radiation (10) and hormone therapy (11). For this reason, metastases from solid tumors, in particular, will re-appear even after initially successful treatments and prolonged periods of complete remission. Further, an unintended consequence of induced cancer cell death is the release of inflammatory cytokines, which can stimulate replication of CSCs (12-14). The percentage of CSCs in the cancer has been shown to increase in patients receiving neoadjuvant chemotherapy (9, 15, 16). Thus, an “equilibrium” may be formed where chemotherapy-induced tumor cell death results in increased stimulation of tumor growth (12). In addition, the cytokines secreted during induced cancer cell death can result in resistance to cytotoxic agents, so that metastases, when they occur, may be refractory to therapy (14, 17, 18). This suggests, for therapy to be effective on a consistent basis, it must eliminate both CSCs and non-stem cell cancer cells. Curcumin and Interleukin-6 (IL-6) IL-6 (also known as interferon (IFN)-β2) is a multi-functional cytokine involved in the immune and inflammatory response and progression from inflammation to cancer. Increased IL-6 activity has been found in multiple cancers, including multiple myeloma, as well as breast, colon and prostate carcinoma, and IL-6 has been associated with decreased survival and more aggressive disease in these patients (19-22). IL-6 signals through a heterodimeric receptor complex that contains the ligand binding IL-6α chain (CD126) and the common cytokine receptor signal-transducing subunit glycoprotein-130 (gp130, CD130) (19, 23). This leads to activation of the JAK family of tyrosine kinases (Janus kinases), which stimulate multiple pathways, including MAPK, STAT-3 and AKT (19, 23-25). IL-6 promotes chemoresistance, angiogenesis and invasion (12, 17, 26-29). Furthermore, IL-6 has been shown to convert regular cancer cells to CSCs in established breast and prostate cancer cell lines (12). When investigators in this latter study added an anti-IL-6 antibody to the culture medium, this did not occur, demonstrating the crucial role of IL-6 in non-stem cell cancer cell to CSC conversion (12). Shi et al. used multiple chemotherapy agents, including 5fluorouracil, paclitaxel and doxorubicin, standard drugs for the 599 This article is freely accessible online. Correspondence to: Lawrence Helson, MD, SignPath Pharma, Inc., 1375 California Road, Quakertown, PA 18951, U.S.A. Tel: +1 2155389996, Fax: +1 2155381245, e-mail: [email protected]