Novel functions for 2‐phenylbenzimidazole‐5‐sulphonic acid: Inhibition of ovarian cancer cell responses and tumour angiogenesis

• Published in: Journal of cellular and molecular medicine 2020-02, Vol.24 (4), p.2688-2700
• Main Authors: Kim, Min Su, Kim, Jae Hyeon, Ahn, Eun‐Kyung, Cho, Young‐Rak, Han, Surim, Lee, Choong‐Hyun, Bae, Gyu‐Un, Oh, Joa Sub, Kim, Kyu‐Bong, Seo, Dong‐Wan
• Format: Article
• Language: English
• Subjects: 2‐phenylbenzimidazole‐5‐sulphonic acid; Adipates - pharmacology; Angiogenesis; Animals; Cell adhesion & migration; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Cyclin-dependent kinase 2; Cyclin-dependent kinase 4; Cyclin-Dependent Kinases - metabolism; Cyclins; Down-Regulation - drug effects; Experiments; Female; G1 phase; G1 Phase - drug effects; Human Umbilical Vein Endothelial Cells; Humans; Imidazoles - pharmacology; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Life sciences; Lotions; Matrix metalloproteinase; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - metabolism; Metalloproteinase; MKK3 protein; Molecular modelling; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Original; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; p38MAPK; Polymerase chain reaction; Protein kinase; Protein Serine-Threonine Kinases - metabolism; Pyridines - pharmacology; Rats; Rats, Sprague-Dawley; Standard deviation; Succinates - pharmacology; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 1582-1838; 1582-4934; 1582-4934
• DOI: 10.1111/jcmm.14989

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 G1 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‐p38MAPK) activity and subsequent down‐regulation of MMP‐2, MMP‐9, Cdk4, Cdk2 and integrin β1, as evidenced by treatment with p38MAPK 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.