We studied the anticancer activity of a series of new combretastatin derivatives with B-ring modifications. The structure-activity relationship (SAR) information confirmed the importance of cis-stereochemistry and of a phenolic moiety in B-ring. We selected the benzo[b]thiophene and benzofuran combretastatin analogues 11 (ST2151) and 13 (ST2179) and their phosphate prodrugs (29 and 30) for their high antitumor activity in in vitro and in vivo models. Cell exposure to IC50 of 11, 13, and CA-4 led to the arrest of various cell types in the G2/M phase of the cell cycle and induction of apoptosis. Mainly, 11 and 13 induced the formation of multinucleated cells with abnormal chromatin distribution, with only a minimal effect on the microtubule organization, with respect to CA-4. Interestingly, both the pharmacokinetic profile of 29 and its in vivo antitumor effect and those of 30, active even after oral administration, suggest additional pharmacological differences between these compounds and CA-4P.
Abstract.We examined the effects of curcumin and of its isoxazole analogue MR 39 in the MCF-7 breast cancer cell line and in its multidrug-resistant (MDR) variant MCF-7R. In comparison with MCF-7, MCF-7R lacks estrogen receptor α (ERα) and overexpressess P-glycoprotein (P-gp), different IAPs (inhibitory of apoptosis proteins) and COX-2. Through analyses of the effects on cell proliferation, cycling and death, we have observed that the antitumor activity of curcumin and of the more potent (approximately two-fold) MR 39 is at least equal in the MDR cell line compared to the parental MCF-7. Similar results were observed also in an MDR variant of HL-60 leukemia. RT-PCR evaluations performed in MCF-7 and MCF-7R showed that curcumin or MR 39 produced early modifications in the amounts of relevant gene transcripts, which, however, were mostly diverse (i.e. represented by decreases in IAPs and COX-2 in MCF-7R versus reductions in Bcl-2 and Bcl-X L as well as increases in the Bcl-X S /Bcl-X L ratio in MCF-7) in the two cell lines. These results could not be explained by an involvement of NF-κB (p65 subunit) or STAT3, since the low nuclear levels of these transcription factors present in MCF-7 were only slightly, though significantly, elevated in MCF-7R; moreover, curcumin or MR 39 caused minor changes in NF-κB or STAT3 activation. Overall, these data underline that curcumin or MR 39 antitumor activities are not hampered by P-gp expression or lack of ERα in breast cancer cells. Remarkably, the agents appeared to modify their molecular effects according to the diverse gene expression patterns existing in the MDR and in the parental MCF-7. Clearly, the structure and properties of curcumin can form the basis for the development of antitumor compounds that are more effective against both chemosensitive and MDR cells.
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.
A novel class of combretastatins, modified at A-ring or both A- and B-rings, mainly by replacement with benzofuran or benzo[b]thiophene, were synthesized. The new heterocombretastatins showed good cytotoxic activity on BMEC and H-460 cell lines. The aminocombretastatin 9f potently inhibits cell growth of BMEC and combretastatin-resistant HT-29 cell lines, with potential interest to treat colon carcinoma. Heterocombretastatins 9a,b inhibit tubulin polymerization similarly to CA-4 by having a binding to colchicine site five times stronger.
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