The antitumor activities of curcumin and of its isoxazole analogue are not affected by multiple gene expression changes in an MDR model of the MCF-7 breast cancer cell line: Analysis of the possible molecular basis

Abstract

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.

Potential antiproliferative effect of isoxazolo- and thiazolo coumarin derivatives on breast cancer mediated bone and lung metastases

“…Based on the »hard and so (Lewis) acids and bases« (HSAB) concept that electrophiles a ack the coumarine ring (19), the eight heterocyclic amines, isoxazoles and thiazoles, were derivatized to obtain diazonium ions which would be further used as electrophiles to a ack the coumarine ring at position 3. Isoxazole and thiazole substituents were used based on the literature data pointing to the antiproliferative and tumour vascular-disrupting activity of their derivatives (20)(21)(22)(23), with isoxazole and thiazole rings being important pharmacophores. Their anticancer eff ects were demonstrated in vivo (23) and in vitro (24-26) using various cancer cell lines, including breast cancer cells.…”

“…Isoxazole and thiazole substituents were used based on the literature data pointing to the antiproliferative and tumour vascular-disrupting activity of their derivatives (20)(21)(22)(23), with isoxazole and thiazole rings being important pharmacophores. Their anticancer eff ects were demonstrated in vivo (23) and in vitro (24-26) using various cancer cell lines, including breast cancer cells. Hence, a superior cellular eff ect was expected in comparison with 4-hydroxycoumarin as a reference.…”

Virtual Screening of potential inhibitors from Herbs for the treatment of Breast Cancer

“…Curcumin has been shown to exhibit antioxidant, anti-inflammatory, antimicrobial, and anticarcinogenic activities. Several studies suggested that cyclocurcumin compound were found to be inhibiting proliferation of breast cancer cells [26][27][28].…”

Perspectives on New Synthetic Curcumin Analogs and their Potential Anticancer Properties

“…Poma et al [66] have also examined the effects of curcumin and compound 63 in the MCF-7 breast cancer cell line, and in its multi-drug resistant variant MCF-7R, which lacks estrogen receptor alpha (ER-) and exhibits over-expression of P-glycoprotein (P-gp), IAP (inhibitory of apoptosis proteins) and COX-2 proteins. It was observed that the anti-tumor activity of curcumin and compound 63 is equivalent in the MDR cell line.…”