Abstract A002: Bcl-2–Dependent Apoptotic Resistance Overcome by (2-Methylbutyryl) Shikonin Through ROS-Driven Mitochondrial Signaling in Melanoma

Abstract

Skin cancer is one of the most common forms of cancer worldwide, among which melanoma represents the most aggressive and lethal subtype due to its high metastatic potential and resistance to apoptosis. A critical factor underlying melanoma progression and survival is the dysregulation of apoptotic pathways, particularly the overexpression of the anti-apoptotic protein Bcl-2, which enables tumor cells to evade programmed cell death. Therefore, targeting Bcl-2–mediated survival signaling represents a promising therapeutic approach in melanoma treatment. (2-Methylbutyryl) Shikonin (BSHK), a naturally occurring naphthoquinone derivative, has emerged as a potential anti-cancer agent due to its ability to inhibit cancer cell proliferation and induce apoptosis. The present study aimed to investigate the anti-melanoma potential of BSHK with a specific focus on its modulation of Bcl-2–dependent apoptotic pathways. Biological effects were evaluated using MTT assay, Annexin-V/FITC staining, and immunoblotting analysis. The findings revealed that BSHK significantly inhibited melanoma cell growth and viability while inducing a marked increase in intracellular ROS levels. Importantly, BSHK treatment triggered apoptosis in melanoma cells, as evidenced by enhanced Annexin-V positivity. At the molecular level, BSHK markedly downregulated the expression of Bcl-2, while upregulating pro-apoptotic proteins such as BAX and cleaved Caspase-3, thereby shifting the balance toward apoptosis. In conclusion, (2-Methylbutyryl) Shikonin exerts potent anti-melanoma effects primarily through the suppression of Bcl-2–mediated survival pathways and activation of intrinsic apoptotic signaling. These findings highlight BSHK as a promising candidate for targeting apoptosis resistance in melanoma. AALIM MAQSOOD. BHAT, Sheikh Tasduq. Abdullah. Bcl-2–Dependent Apoptotic Resistance Overcome by (2-Methylbutyryl) Shikonin Through ROS-Driven Mitochondrial Signaling in Melanoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr A002.