In Silico Molecular Docking of 2‐Hydroxyanthraquinone‐Substituted Spiro‐/Ansa Cyclotriphosphazenes: Targeting Apoptosis via Heat Shock Protein Modulation in Breast and Colon Cancer Cells

Cancer research takes a long time and is complex. Preclinical studies prove that compounds can be potential anticancer agents and contribute to cancer studies. Overexpression of survivin may cause decreased sensitivity of anticancer agents and antiapoptotic activation through its excretion from cells via MDR. Anthraquinones and phosphazene compounds, which are among the active biological compounds and identified in many studies on cancer, come to the fore in biochemical, microbiological, and pharmacological studies. In this study, it was aimed to investigate the effect of 2-hydroxyanthraquinone-substituted spiro-/ansa cyclotriphosphazene compounds (II-VIII) on multidrug resistance, ER stress, and apoptotic cell death pathways in breast and colon cancer cells. mRNA expressions of multidrug resistance transporter, ER stress, heat shock, and apoptotic genes assessed by qPCR. Besides protein levels of apoptosis, cell cycle and related signaling pathways (CASP3, BCL-w, sTNF-R, cIAP-2, TRAILRs, IGFBPs, Survivin, XIAP, etc.) were determined by antibody membrane array method in MCF-7 and DLD-1 cell lines. To elucidate the activities of Survivin protein-related compounds, in silico-mediated molecular docking studies were evaluated. ABCs, HSPs, and GRPs gene expressions in MCF-7 and DLD-1 cells were decreased by these compounds. Besides, in gene regulations of apoptosis and signaling pathways, it was observed that the compounds induce overexpression of BAX and underexpression BCL-2. In addition, especially survivin expression was downregulated by all the compounds. It has been determined that the compounds eliminate multidrug resistance in breast and colon cancer cells, suppress HSPs and GRPs genes, and lead the cells to death, especially through the antiapoptotic pathway Survivin. These compounds can be evaluated and developed as Survivin inhibitor agents in anticancer studies.