Department of Pharmacy, College of Pharmacy, Dankook University, Cheonan, Korea.
Biocenter, Gyeonggi Business & Science Accelerator, Suwon, Korea.
J Cell Mol Med. 2020 Feb;24(4):2688-2700. doi: 10.1111/jcmm.14989. Epub 2020 Jan 20.
In this study, we investigated the effects and molecular mechanisms of 2-phenylbenzimidazole-5-sulphonic acid (PBSA), an ultraviolet B protecting agent used in sunscreen lotions and moisturizers, on ovarian cancer cell responses and tumour angiogenesis. PBSA treatment markedly blocked mitogen-induced invasion through down-regulation of matrix metalloproteinase (MMP) expression and activity in ovarian cancer SKOV-3 cells. In addition, PBSA inhibited mitogen-induced cell proliferation by suppression of cyclin-dependent kinases (Cdks), but not cyclins, leading to pRb hypophosphorylation and G phase cell cycle arrest. These anti-cancer activities of PBSA in ovarian cancer cell invasion and proliferation were mediated by the inhibition of mitogen-activated protein kinase kinase 3/6-p38 mitogen-activated protein kinase (MKK3/6-p38 ) activity and subsequent down-regulation of MMP-2, MMP-9, Cdk4, Cdk2 and integrin β1, as evidenced by treatment with p38 inhibitor SB203580. Furthermore, PBSA suppressed the expression and secretion of vascular endothelial growth factor in SKOV-3 cells, leading to inhibition of capillary-like tubular structures in vitro and angiogenic sprouting ex vivo. Taken together, our results demonstrate the pharmacological effects and molecular targets of PBSA on modulating ovarian cancer cell responses and tumour angiogenesis, and suggest further evaluation and development of PBSA as a promising chemotherapeutic agent for the treatment of ovarian cancer.
在这项研究中，我们调查了 2-苯并咪唑-5-磺酸（PBSA）的作用和分子机制，PBSA 是一种用于防晒霜和保湿霜的紫外线 B 保护剂，对卵巢癌细胞反应和肿瘤血管生成有影响。PBSA 处理明显通过下调基质金属蛋白酶（MMP）的表达和活性来阻止有丝分裂原诱导的侵袭，在卵巢癌细胞 SKOV-3 中。此外，PBSA 通过抑制细胞周期蛋白依赖性激酶（Cdks）而不是细胞周期蛋白抑制有丝分裂原诱导的细胞增殖，导致 pRb 低磷酸化和 G1 期细胞周期停滞。PBSA 在卵巢癌细胞侵袭和增殖中的这些抗癌活性是通过抑制丝裂原激活蛋白激酶激酶 3/6- p38 丝裂原激活蛋白激酶（MKK3/6-p38）活性和随后下调 MMP-2、MMP-9、Cdk4、Cdk2 和整合素β1 来介导的，这一点可以通过用 p38 抑制剂 SB203580 处理来证明。此外，PBSA 抑制 SKOV-3 细胞中血管内皮生长因子的表达和分泌，导致体外毛细血管样管状结构和体内血管生成芽的抑制。总之，我们的结果表明 PBSA 对调节卵巢癌细胞反应和肿瘤血管生成的药理作用和分子靶点，并表明进一步评估和开发 PBSA 作为治疗卵巢癌的有前途的化疗药物。
