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

Abstract

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.

Broussonin A– and B–mediated inhibition of angiogenesis by blockade of VEGFR‐2 signalling pathways and integrin β1 expression

“…The experimental procedures were approved by the Institutional Animal Care and Use Committee at Dankook University (Cheonan, Republic of Korea). Thoracic aortic ring segments embedded in Matrigel ® were pretreated with broussonin A or B (10 µM) for 30 min, followed by VEGF‐A (500 ng/mL) for 3 days and then incubated with fresh broussonin A or B plus VEGF‐A every other day, and photographed on the 7 th day using x40 objective magnification 28 …”

“…Thoracic aortic ring segments embedded in Matrigel ® were pretreated with broussonin A or B (10 µM) for 30 min, followed by VEGF-A (500 ng/mL) for 3 days and then incubated with fresh broussonin A or B plus VEGF-A every other day, and photographed on the 7 th day using x40 objective magnification. 28 The area of microvessel sprouting was quantified using Adobe PhotoShop software.…”

Dissection of the MKK3 Functions in Human Cancer: A Double-Edged Sword?

“…MKK3 inhibition reduces furin expression and cell motility [17]. Kim et al, found MKK3 to sustain cell motility and angiogenesis through essential molecular key players (MMP-2, MMP-9, Cdk4, Cdk2, and integrin β1) in SKOV-3 cells [18]. Kang et al, demonstrated that ectopic MKK3 drives paclitaxel resistance by inducing p-glycoprotein expression in Heya8 and Skov3ip1 cells, suggesting the involvement of MKK3-p38MAPK pathway activation in ovarian cancer drug resistance [19].…”