Photodynamic therapy (PDT) provides an effective cancer treatment option but it requires sufficient cellular oxygen concentration to exert its photosensitizing effects. Due to hypoxic nature of most tumors, widespread clinical application of PDT is restricted and warrants development of photosensitizers which can kill cancer cells in ROS independent manner. Previously, we reported significant enhancement of the anti-cancer property of coralyne in presence of ultraviolet-A (UVA) light exposure against several human carcinoma cell lines. This study aimed at unravelling molecular cascades of events in CUVA treatment (coralyne and UVA light)-mediated photosensitization of human skin cancer. The CUVA-treatment caused robust apoptosis of A431 cancer cells, primarily through mitochondrial and lysosomal dysfunctions. Silencing of BAX conferred a significant protection against CUVA-induced apoptosis. Both lysosomal proteases and caspase-8 activation contributed to BID cleavage. Further, our results revealed that a dual signaling axis e.g., ATR-p38 MAPK and JAK2-STAT1 pathways functioned upstream of BAX activation in apoptosis response. Moreover, transient silencing of ATR and pharmacological inhibition of p38-MAPK or JAK2 significantly abolished the effect of CUVA treatment induced BAX expression and cell death, linking the extrinsic and intrinsic pathways with the observed cell death. Our data suggest that coralyne, which is known topoisomerase-I inhibitor, may be an attractive agent for photo-chemotherapeutic treatment of human skin cancers.

光动力疗法（PDT）提供了有效的癌症治疗选择，但它需要足够的细胞氧浓度来发挥其光敏作用。由于大多数肿瘤的低氧特性，PDT的广泛临床应用受到了限制，并保证了光敏剂的开发，这些光敏剂可以以ROS独立的方式杀死癌细胞。以前，我们报道了在紫外线A（UVA）照射下针对几种人类癌细胞系存在的情况下，珊瑚烯的抗癌性能显着增强。这项研究旨在阐明CUVA治疗中事件的分子级联反应（c口服和UVA光）介导的人类皮肤癌的光敏性。CUVA处理主要通过线粒体和溶酶体功能障碍引起A431癌细胞的强大凋亡。BAX沉默赋予了针对CUVA诱导的细胞凋亡的显着保护作用。溶酶体蛋白酶和caspase-8激活均有助于BID裂解。此外，我们的结果表明，双重信号轴，例如ATR-p38 MAPK和JAK2-STAT1通路在凋亡反应中BAX激活的上游起作用。此外，ATR的瞬时沉默和对p38-MAPK或JAK2的药理抑制显着消除了CUVA治疗诱导的BAX表达和细胞死亡的影响，将外在和内在途径与观察到的细胞死亡联系起来。我们的数据表明，已知的拓扑异构酶-I抑制剂coralyne，