Department of Pharmacy, Guangzhou Institute of Dermatology, Guangzhou, Guangdong 510095, P.R. China.
Department of Urology, Minimally Invasive Surgery Centre, Guangzhou Urology Research Institute, Guangdong Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510230, P.R. China.
Mol Med Rep. 2021 Jan;23(1). doi: 10.3892/mmr.2020.11678. Epub 2020 Nov 12.
Melanoma is one of the most aggressive forms of skin tumour with poor prognosis; no effective therapy has been established for melanoma at the metastatic stage. The present study aimed to investigate the role of poly (ADP ribose) polymerase (PARP) inhibitors (PARPis) and PARP1 expression in melanoma progression. In addition, whether high PARP1 expression was associated with poor overall survival in melanoma, and whether a combination effect existed between PARPis and other anti‑tumour compounds (e.g., sunitinib) was analysed. The PARP1 expression was detected using western blot analysis and the proliferation of cells was detected with a colony formation assay. In addition, cell viability assays and xenograft tumor experiments were conducted. The results of the present study demonstrated that sunitinib reduced PARP1 expression and proliferation of melanoma cells. Notably, one of the PARPis, veliparib, reversed the inhibitory effect of sunitinib on PARP1 expression and proliferation, indicating that inhibition of PARP1 enzyme activity by PARPi may be different from the inhibition of PARP1 expression in melanoma cell biological function. To further confirm the relationship between PARP1 expression and tumour cell proliferation, seven compounds, including common approved drugs and natural Chinese medicine monomers, were screened, and the results demonstrated that simvastatin and tanshinone I exerted an inhibitory effect on PARP1 expression and melanoma cell proliferation, and their combination was more effective than simvastatin alone in vivo. The results indicated that simvastatin and tanshinone I inhibited melanoma and renal tumour cells by regulating PARP1 expression, and in addition to the enzyme activity of PARP1, the expression of PARP1 protein may serve a role in tumour progression.
黑色素瘤是预后最差的侵袭性皮肤肿瘤之一；转移性黑色素瘤尚无有效的治疗方法。本研究旨在探讨聚（ADP 核糖）聚合酶（PARP）抑制剂（PARPi）和 PARP1 表达在黑色素瘤进展中的作用。此外，还分析了高 PARP1 表达与黑色素瘤患者总生存期不良之间的关系，以及 PARPi 与其他抗肿瘤化合物（如舒尼替尼）之间是否存在联合效应。采用 Western blot 分析检测 PARP1 表达，采用集落形成实验检测细胞增殖。此外，还进行了细胞活力检测和异种移植肿瘤实验。本研究结果表明，舒尼替尼降低了黑色素瘤细胞中 PARP1 的表达和增殖。值得注意的是，PARPi 中的一种 veliparib 逆转了舒尼替尼对 PARP1 表达和增殖的抑制作用，表明 PARPi 抑制 PARP1 酶活性可能与抑制黑色素瘤细胞生物学功能中的 PARP1 表达不同。为了进一步证实 PARP1 表达与肿瘤细胞增殖之间的关系，筛选了包括常用批准药物和天然中药单体在内的七种化合物，结果表明辛伐他汀和丹参酮 I 抑制 PARP1 表达和黑色素瘤细胞增殖，且二者联合作用比辛伐他汀单独作用更有效体内。结果表明，辛伐他汀和丹参酮 I 通过调节 PARP1 表达抑制黑色素瘤和肾肿瘤细胞，除了 PARP1 的酶活性外，PARP1 蛋白的表达可能在肿瘤进展中发挥作用。
