Abstract
We examined anti-tumor effects of zoledronic acid (ZOL), one of the bisphosphonates agents clinically used for preventing loss of bone mass, on human mesothelioma cells bearing the wild-type p53 gene. ZOL-treated cells showed activation of caspase-3/7, -8 and -9, and increased sub-G1 phase fractions. A combinatory use of ZOL and cisplatin (CDDP), one of the first-line anti-cancer agents for mesothelioma, synergistically or additively produced the cytotoxicity on mesothelioma cells. Moreover, the combination achieved greater anti-tumor effects on mesothelioma developed in the pleural cavity than administration of either ZOL or CDDP alone. ZOL-treated cells as well as CDDP-treated cells induced p53 phosphorylation at Ser 15, a marker of p53 activation, and up-regulated p53 protein expression levels. Down-regulation of p53 levels with siRNA however did not influence the ZOL-mediated cytotoxicity but negated the combinatory effects by ZOL and CDDP. In addition, ZOL treatments augmented cytotoxicity of adenoviruses expressing the p53 gene on mesothelioma. These data demonstrated that ZOL-mediated augmentation of p53, which was not linked with ZOL-induced cytotoxicity, played a role in the combinatory effects with a p53 up-regulating agent, and suggests a possible clinical use of ZOL to mesothelioma with anti-cancer agents.
Highlights
The majority of mesothelioma development is tightly linked with occupational asbestos exposure and the patient numbers are increasing worldwide [1,2]
In this study we demonstrated that zoledronic acid (ZOL) alone and the combination with CDDP produced anti-tumor effects on mesothelioma
Down-regulated p53 levels on the other hand negated the synergistic actions by ZOL and CDDP, indicating that the ZOL-induced p53 activation contributed to the combinatory anti-tumor effects produced with CDDP
Summary
The majority of mesothelioma development is tightly linked with occupational asbestos exposure and the patient numbers are increasing worldwide [1,2]. 70–80% of mesothelioma cells have the wild-type p53 gene but show a homologous deletion at the INK4A/ARF locus containing the p14ARF and the p16INK4A genes, which leads to decreased p53 functions despite the wild-type genotype [3,4,5]. Extrapleural pneumonectomy is applicable only for the patients in an early clinical stage and mesothelioma is essentially resistant to radiation. A combination of cisplatin (CDDP) and pemetrexed is currently the first-line regimen but an average survival period with the agents is about 12 months [7]. The clinical outcome even with the updated combinatory chemotherapy is unsatisfactory and a possible second-line agent has not yet been known. A novel therapeutics is thereby required and restoration of decreased p53 functions is one of the strategies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
