In developed countries, cancer is the second leading cause of death, with colon and prostate cancer belonging to the group of most often diagnosed types of neoplastic diseases. The search for new treatment strategies against these types of cancer is thus of top current interest. In this context, salinomycin (SAL), a naturally occurring polyether ionophore, has been identified recently as a very promising anticancer drug candidate towards several tumour cells. In the present work, a broad library of 24 derivatives of C20-epi-salinomycin (2), including C1 singly, C20 singly and C1/C20 doubly modified analogue structures, was screened to identify compounds with improved activity against colon and prostate cancer cells. Our study demonstrated that the growth inhibitory potency of the parent compound on both primary and metastatic colon cancer cells was similar to that of the semisynthetic products derived from SAL, and simultaneously the SAL analogues showed more potent toxic action on metastatic prostate cancer cells than that of the chemically unmodified ionophore. In contrast to the widely used oncological drug doxorubicin, some of the SAL derivatives demonstrated promising anticancer activity with no toxic effects on non-tumour cells, and with more favourable cytotoxicity than that of a reference agent 5-fluorouracil. Mechanistically, the SAL analogues induced late apoptosis in colon cancer cells and necrosis in prostate cancer cells, as well as reduced secretion of interleukin 6 (IL-6) in these cells.
Keywords: Antiproliferative activity; Apoptosis; Colon cancer; Interleukin 6; O-acylated derivatives; Polyether ionophores; Prostate cancer.
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