Lee Jae Hyeop, Choi Byeoung-Kyu, Kim Minsoo, Shin Hee Jae, Park Sun Joo
BB21 Plus Program, Department of Chemistry, Pukyong National University, Busan 48513, Republic of Korea.
Department of Bio-Convergence Engineering, Dongyang Mirae University, Seoul 08221, Republic of Korea.
Mar Drugs. 2024 Nov 28;22(12):533. doi: 10.3390/md22120533.
Melanoma is an aggressive skin cancer with a high risk of cancer-related deaths, and inducing apoptosis in melanoma cells is a promising therapeutic strategy. This study investigates the anti-tumor potential of a novel lucknolide derivative LA-UC as a therapeutic candidate for melanoma. Lucknolide A (LA), a tricyclic ketal-lactone metabolite isolated from marine-derived sp., was chemically modified by introducing a 10-undecenoyl group to synthesize LA-UC. LA-UC preferentially inhibited the proliferation of melanoma cells, including B16F10, while exerting minimal effects on normal melanocytes or other tumor cell types, indicating the selective action of LA-UC against melanoma cells. LA-UC decreased G2/M checkpoint proteins, including cyclin B1 and Cdc2, while activating caspase-3 and caspase-9, resulting in G2/M cell cycle arrest and inducing apoptotic cell death in B16F10 cells. The addition of a pan-caspase inhibitor confirmed the caspase-dependent mechanism of LA-UC-induced cell death. Additionally, LA-UC elevated mitochondrial ROS levels, leading to mitochondrial membrane disruption, upregulation of pro-apoptotic proteins, and DNA damage in melanoma cells. The ROS scavenger N-acetylcysteine reduced LA-UC-induced mitochondrial ROS accumulation, mitochondrial membrane disruption, DNA damage, and apoptosis. Collectively, these findings suggest that LA-UC induces G2/M cell cycle arrest and caspase-dependent apoptosis in B16F10 cells through excessive mitochondrial ROS generation, membrane impairment, and DNA damage, highlighting its potential as a promising therapeutic candidate for melanoma treatment.
黑色素瘤是一种侵袭性皮肤癌，与癌症相关的死亡风险很高，诱导黑色素瘤细胞凋亡是一种很有前景的治疗策略。本研究调查了一种新型鲁克诺内酯衍生物LA-UC作为黑色素瘤治疗候选药物的抗肿瘤潜力。鲁克诺内酯A（LA）是从海洋来源的 中分离出的一种三环缩酮内酯代谢物，通过引入10-十一碳烯酰基进行化学修饰以合成LA-UC。LA-UC优先抑制黑色素瘤细胞（包括B16F10）的增殖，而对正常黑素细胞或其他肿瘤细胞类型的影响最小，表明LA-UC对黑色素瘤细胞具有选择性作用。LA-UC降低了G2/M检查点蛋白，包括细胞周期蛋白B1和Cdc2，同时激活了半胱天冬酶-3和半胱天冬酶-9，导致G2/M细胞周期停滞并诱导B16F10细胞凋亡。添加泛半胱天冬酶抑制剂证实了LA-UC诱导细胞死亡的半胱天冬酶依赖性机制。此外，LA-UC提高了线粒体ROS水平，导致线粒体膜破坏、促凋亡蛋白上调以及黑色素瘤细胞中的DNA损伤。ROS清除剂N-乙酰半胱氨酸减少了LA-UC诱导的线粒体ROS积累、线粒体膜破坏、DNA损伤和细胞凋亡。总的来说，这些发现表明LA-UC通过过量产生线粒体ROS、膜损伤和DNA损伤诱导B16F10细胞发生G2/M细胞周期停滞和半胱天冬酶依赖性凋亡，突出了其作为黑色素瘤治疗有前景的候选药物的潜力。
