Exploring Synergistic Potential of Sorafenib and Atorvastatin to Launch Apoptosis and Ferroptosis-driven Mixed Cell Death Mechanism in Colorectal Cancer.

Colorectal cancer (CRC) is a third leading cause of death and is often recognised by a higher mutation burden. The standard clinical regimen for CRC chiefly focuses on targeting a single-cell death mechanism, which encounters constraints such as resistance, chronic toxicity, and suboptimal efficacy. Thus, triggering a hybrid cell death mechanism that acts through distinct pathways offers a promising avenue in CRC management. The present investigation explores the combined therapy of Sorafenib (SOR) and Atorvastatin (ATST) to induce a dual cell death mechanism, specifically ferroptosis and classic apoptosis, in colon cancer cells. The combination of ATST + SOR at a 1:1 ratio showed a combination index value of < 1 and a dose reduction index > 1 in HT29, HCT116, CT26, and SW480 cell lines. In-vitro studies with a synergistic combination of ATST + SOR showed amplified levels of MDA, ROS, and membrane depolarisation, while diminishing antioxidant levels. The cell migration, cell-invasion, and wound healing assays revealed the anti-metastatic potential of the combination. In-vivo efficacy study revealed marked reduction in disease manifestations with tumor growth inhibition rate of ~ 80%. Unfortunately, the toxicity study revealed the presence of systemic, organ, and hemolytic toxicity. In a nutshell, the proposed combination of ATST and SOR presents a compelling strategy to trigger a dual cell death mechanism, thereby amplifying the efficacy and anti-metastatic potential in CRC. Nonetheless, the safety concerns warrant continued investigation into advanced drug delivery systems to boost efficacy and clinical usage of the present combination.