Synthesis and in vitro biological evaluation of thiosulfinate derivatives for the treatment of human multidrug-resistant breast cancer

Abstract

<p>Organosulfur compounds derived from <i>Allium</i> vegetables have long been recognized for various therapeutic effects, including anticancer activity. Allicin, one of the main biologically active components of garlic, shows promise as an anticancer agent; however, instability makes it unsuitable for clinical application. The aim of this study was to investigate the effect of stabilized allicin derivatives on human breast cancer cells <i>in vitro</i>. In this study, a total of 22 stabilized thiosulfinate derivatives were synthesized and screened for their in vitro antiproliferative activities against drug-sensitive (MCF-7) and multidrug-resistant (MCF-7/Dx) human adenocarcinoma breast cancer cells. Assays for cell death, apoptosis, cell cycle progression and mitochondrial bioenergetic function were performed. Seven compounds (<b>4b</b>, <b>7b</b>, <b>8b</b>, <b>13b</b>, <b>14b</b>, <b>15b</b> and <b>18b</b>) showed greater antiproliferative activity against MCF-7/Dx cells than allicin. These compounds were also selective towards multidrug-resistant (MDR) cells, a consequence attributed to collateral sensitivity. Among them, <b>13b</b> exhibited the greatest anticancer activity in both MCF-7/Dx and MCF-7 cells, with IC₅₀ values of 18.54±0.24 and 46.50±1.98 μmol/L, respectively. <b>13b</b> altered cellular morphology and arrested the cell cycle at the G₂/M phase. Additionally, <b>13b</b> dose-dependently induced apoptosis, and inhibited cellular mitochondrial respiration in cells at rest and under stress. MDR presents a significant obstacle to the successful treatment of cancer clinically. These results demonstrate that thiosulfinate derivatives have potential as novel anticancer agents and may offer new therapeutic strategies for the treatment of chemoresistant cancers.</p>