Diindolylmethane Derivatives: New Selective Blockers for T-Type Calcium Channels

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_V3.3 (IC₅₀s DIM 2.09 µM; DIM-one 9.07 µM) while compound IX inhibited both Ca_V3.2 (6.68 µM) and Ca_V3.3 (IC₅₀ = 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 Ca²⁺ current through Ca_V3.1 (IC₅₀ = 8.32 µM) and Ca_V3.3 (IC₅₀ = 9.63 µM), while IX partially blocked Ca_V3.2 and Ca_V3.3 inward Ca²⁺ current. In contrast, DIM-one preferentially blocked Ca_V3.1 inward Ca²⁺ current (IC₅₀ = 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.