ASC-J9誘導人類黑色素瘤細胞凋亡之機轉探討

黑色素瘤 (melanoma) 的發病率雖然僅占皮膚癌的1%，但在皮膚癌的死亡人口中有80%以上都是來自黑色素瘤，故黑色素瘤是一種具高度侵襲性的皮膚惡性腫瘤之一。黑色素瘤患者在中晚期的存活率並不理想，因此目前急需研究新的輔助藥物來提升治療的效果。二甲基薑黃素 (Dimethylcurcumin)，開發代號ASC-J9，是一種選擇性雄性激素受體 (androgen receptor, AR) 的降解劑，目前已有許多研究證實ASC-J9在前列腺癌中展現出多重的抗癌機制，但顯少有研究證實ASC-J9和黑色素瘤之間的關係。本實驗選用了兩株人類黑色素瘤細胞A375、A2058，實驗結果顯示隨著ASC-J9加藥濃度上升，細胞存活率下降、染色質濃縮聚集的比例增加、往早期和晚期凋亡移動的趨勢、DNA片斷化讓細胞週期sub-G1 phase增加、細胞內ROS含量上升、內質網壓力上升、粒線體膜電位下降。Western blot的結果顯示，切割位的caspase 9、3、6、7蛋白表現量增加，證實ASC-J9會誘導黑色素瘤細胞走向內源性的細胞凋亡。

Although accounting for only 1% of all skin cancers, melanoma is responsible for over 80% of skin cancer deaths, rendering it one of the most aggressive skin malignancies. The survival rate of patients with advanced melanoma remains unsatisfactory; therefore, the development of novel adjuvant agents to enhance treatment efficacy demands urgent attention. Dimethylcurcumin (ASC-J9) is a selective androgen receptor degradation enhancer. Many studies have demonstrated its multiple anticancer mechanisms in prostate cancer; however, the relationship between ASC-J9 and melanoma remains poorly understood. In this study, the human melanoma cell lines A 375 and A2058 were treated with ASC-J9. The results showed that increasing concentrations of ASC-J9 progressively decreased cell viability and increased the proportion of cells exhibiting chromatin condensation. Furthermore, flow cytometric analysis demonstrated a significant increase in both early and late apoptotic cell populations, while cell cycle analysis revealed an increased sub-G1 population, indicating enhanced DNA fragmentation. In addition, ASC-J9 treatment increased intracellular ROS levels and induced ER stress, while decreasing mitochondrial membrane potential. Western blot analysis further revealed that ASC-J9 treatment increased the levels of cleaved caspase-9, caspase-3, caspase-6, and caspase-7. Taken together, these findings demonstrate that ASC-J9 induces apoptosis in melanoma cells through the intrinsic apoptotic pathway.