Computational and biological insights for anti-cancer effects of Karanjin through AR/ER modulation, ROS generation and cell cycle arrest in prostate cancer

Prostate cancer (PCa) has become the one of the leading causes of mortality among men as it progresses from an early androgen-dependent to a late (metastatic) androgen-independent form of cancer. Conventional PCa therapy has no promising effect on androgen-independent PCa and have significantly reduced the therapeutic potential. Thereby, there is a need for effective, safer and less toxic treatment options to improve the treatment efficiency. From the past few years, phytochemicals have attracted much attention worldwide due to their wide range of pharmacological properties and their cost-effective and promising approach in inhibiting the growth of cancer. Thereby, for this study, the phytochemical Karanjin isolated from Pongamia pinnata has been chosen due their safer and wide range of biological activities including anti-tumor, anti-proliferation, anti-angiogenesis and so on. Multiple nuclear receptors (NRs) are involved in PCa pathogenesis including androgen (AR) as well as estrogen receptors (ERα and ERβ). Initially, Karanjin was evaluated for their binding affinity and interaction studies against AR and ER via computer-assisted molecular docking and molecular dynamics simulation methodologies. The results showed effective interactions with the 2Q7I (AR) and 1QKM (ERβ) with a binding energy (BE) of −6.72, and −5.92 kcal/mol, respectively. Karanjin was further evaluated at the cellular and molecular markers of proliferation and apoptosis against human androgen-insensitive (PC-3) PCa cells. In vitro study suggested that Karanjin significantly inhibits the proliferation and invasion of androgen-insensitive PCa by inhibiting cell viability with IC 50 value at 40 μM concentration. The enhanced reactive oxygen species (ROS) production was seen from 38.92 %, to 84.24 % at 30–50 μM, respectively, inducing apoptosis cycle arrest at G2/M phase in PC-3 cells. The study demonstrates that Karanjin suppresses the proliferation, migration and invasion of PC-3 cells with increase in wound area of 46.73 μm–90.19 μm from 30 to50 μM concentrations. Therefore, it is very clear that Karanjin is active against the biological targets and is capable of showing its dual inhibitory action. The study highlights Karanjin's promising anti-cancer effects and aids in the design of multi-target therapeutic agents for PCa.