| Summary: | The natural product indole-3-carbinol (I3C) and its major digestive product 3,3′-diindolylmethane (DIM) have shown clinical promise in multiple forms of cancer including breast cancer. In this study, we explored the calcium channel activity of DIM, its synthetic derivative 3,3′-Diindolylmethanone (DIM-one) and related I3C and DIM-one analogs. For the first time, DIM, DIM-one and analog IX were identified as selective blockers for T-type Ca<sub>V</sub>3.3 (IC<sub>50</sub>s DIM 2.09 µM; DIM-one 9.07 µM) while compound IX inhibited both Ca<sub>V</sub>3.2 (6.68 µM) and Ca<sub>V</sub>3.3 (IC<sub>50</sub> = 3.05 µM) using a FLIPR cell-based assay to measure inhibition of T-type calcium channel window current. Further characterization of DIM by electrophysiology revealed it inhibited inward Ca<sup>2+</sup> current through Ca<sub>V</sub>3.1 (IC<sub>50</sub> = 8.32 µM) and Ca<sub>V</sub>3.3 (IC<sub>50</sub> = 9.63 µM), while IX partially blocked Ca<sub>V</sub>3.2 and Ca<sub>V</sub>3.3 inward Ca<sup>2+</sup> current. In contrast, DIM-one preferentially blocked Ca<sub>V</sub>3.1 inward Ca<sup>2+</sup> current (IC<sub>50</sub> = 1.53 µM). The anti-proliferative activities of these compounds revealed that oxidation of the methylene group of DIM shifted the selectivity of DIMs from breast cancer cell line MCF-7 to colon cancer cell line HT-29.
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