Curcumin as a Possible Lead Compound against Hormone‐Independent, Multidrug‐Resistant Breast Cancer

Abstract

We examine the possible evidence that the phytochemical curcumin may overcome resistance to hormonal and cytotoxic agents in breast cancer. We present our observations on MCF-7R, a multidrug-resistant (MDR) variant of the MCF-7 breast cancer cell line. In contrast to MCF-7, MCF-7R lacks aromatase and estrogen receptor alpha (ERalpha) and overexpresses the multidrug transporter ABCB1 and the products of different genes implicated in cell proliferation and survival, like c-IAP-1, NAIP, survivin, and COX-2. Nevertheless, in cytotoxicity and cell death induction assays, we found that the antitumor activity of curcumin is substantial both in MCF-7 and in MCF-7R. We elaborated the diketone system of curcumin into different analogues; the benzyloxime and the isoxazole and pyrazole heterocycles showed remarkable increases in the antitumor potency both in the parental and in the MDR MCF-7 cells. Furthermore, curcumin or, more potently, the isoxazole analogue, produced early reductions in the amounts of relevant gene transcripts that were diverse (i.e., they were relative to Bcl-2 and Bcl-X(L) in MCF-7 and the inhibitory of apoptosis proteins and COX-2 in MCF-7R) in the two cell lines. Thus, the two compounds exhibited the remarkable property of being able to modify their molecular activities according to the distinct characteristics of the parental and MDR cells. We discuss also how curcumin may (1) exert antitumor effects in breast cancer through ER-dependent and ER-independent mechanisms; and (2) act as a drug transporter-mediated MDR reversal agent. Overall, the structure of curcumin may represent the basis for the development of new, effective anticancer agents in hormone-independent MDR breast cancer.

PAC, a novel curcumin analogue, has anti-breast cancer properties with higher efficiency on ER-negative cells

“…Furthermore, it has been recently shown that curcumin induces immuno-restoration in tumour-bearing animals [5], indicating that the inclusion of this natural product in therapeutic regimens against cancer should be beneficial for great proportion of cancer patients, including those afflicted with breast carcinoma. Indeed, several publications have reported the anti-carcinogenic activity of curcumin against various breast cancer cell lines, including the multidrug-resistant ones [6][7][8]. Furthermore, numerous in vivo studies have shown its chemo-preventive effect against breast cancer [9].…”

Carboplatin resistant human laryngeal carcinoma cells are cross resistant to curcumin due to reduced curcumin accumulation

“…The drugs that could be efficient against chemoresistant cells could be of great importance in enhancing effectiveness of cancer treatment. There are some data in the literature that verified anticancer properties of curcumin in drug resistant cells (Labbozzetta et al, 2009;Lu et al, 2012;Sung et al, 2009;Weir et al, 2007). However, these data should be more abundant in order to make more general conclusions about curcumin's activity against drug resistant cells.…”

“…This was shown for multidrug resistant myeloid leukemia cells (Lu et al, 2012), cisplatin resistant ovarian cancer cells (Weir et al, 2007), multiple myeloma cells resistant to 4 4 dexamethasone, doxorubicin and melphalan (Sung et al, 2009), as well as hormone independent, multidrug resistant breast cancer cells (Labbozzetta et al, 2009). …”

Perspectives on Chemopreventive and Therapeutic Potential of Curcumin Analogs in Medicinal Chemistry

“…Recently, Curcumin analogs such as pyrazole and isoxazole 28 (Scheme 1 ) has been synthesized and evaluated for their anticancer activity. Both the analogs were found to possess enhanced anti-tumor potency against MCF-7 and MDR-transfected MCF-7 breast cancer cells [71, 72]. Furthermore, they reduced the expression levels of Bcl-2, Bcl-X L , and COX-2 in the breast cancer cells.…”

“…Furthermore, they reduced the expression levels of Bcl-2, Bcl-X L , and COX-2 in the breast cancer cells. These results suggest that these analogs could be effective anticancer agents for the treatment of hormone-independent MDR breast cancer [72]. In another report, electron-rich pyrazole and isoxazole analogs were synthesized and evaluated against two hormone-dependent and independent breast cancer cell lines [71].…”