Hospital for Skin Disease, Institute of Dermatology, Chinese Academy of Medical Science, Peking Union Medical College, Nanjing 210042, PR China.
Hospital for Skin Disease, Institute of Dermatology, Chinese Academy of Medical Science, Peking Union Medical College, Nanjing 210042, PR China.
Eur J Pharmacol. 2019 May 15;851:174-185. doi: 10.1016/j.ejphar.2019.03.004. Epub 2019 Mar 2.
Malignant melanoma was the leading cause of mortality among the skin-associated cancer owing to its highly metastatic feature, increasing incidence and drug resistance requirement. Retinoids played important roles in the treatment of cancer via the activation of retinoid acid receptor (RAR) or retinoid X receptor (RXR). Our present study showed that the third-generation retinoid adapalene exhibited strong inhibitory effects on the proliferation of melanoma cells than other retinoids, such as all-trans-retinoic acid (ATRA), isotretinoin, acitretin and bexarotene, and adapalene exerted significant inhibitory effects on the colony formation of melanoma cells. Further study confirmed that adapalene treatment triggered dramatic S phase arrest and apoptosis, and S phase arrest was the potential mechanism of apoptosis induction. In addition, adapalene treatment dramatically regulated the expression of S phase-related protein, and increased the protein level of DNA damage marker，which were consistent with the results of the induction of the tail moment in comet assays. Meanwhile, DNA damage response was activated and the DNA repair pathway was simultaneously inhibited by adapalene treatment, which might furtherly potentiate S phase arrest and subsequent apoptosis. Taken together, these results showed that adapalene exhibited strong anti-cancer activity, and might be a candidate agent for the clinical treatment of melanoma.
恶性黑色素瘤因其高转移性、发病率增加和耐药性要求，成为皮肤相关癌症死亡的主要原因。类视黄醇通过激活视黄酸受体 (RAR) 或视黄醇 X 受体 (RXR)，在癌症治疗中发挥重要作用。本研究表明，第三代类视黄醇阿达帕林比其他类视黄醇（如全反式维甲酸 (ATRA)、异维 A 酸、阿维 A 酯和贝沙罗汀）对黑色素瘤细胞的增殖具有更强的抑制作用，阿达帕林对黑色素瘤细胞的集落形成具有显著的抑制作用。进一步的研究证实，阿达帕林处理触发了明显的 S 期阻滞和细胞凋亡，而 S 期阻滞是诱导细胞凋亡的潜在机制。此外，阿达帕林处理显著调节了 S 期相关蛋白的表达，并增加了 DNA 损伤标志物的蛋白水平，这与彗星试验中诱导的尾部矩结果一致。同时，阿达帕林处理激活了 DNA 损伤反应并抑制了 DNA 修复途径，这可能进一步增强 S 期阻滞和随后的细胞凋亡。总之，这些结果表明阿达帕林具有很强的抗癌活性，可能是治疗黑色素瘤的临床候选药物。
