Keishiro Tomoda1, Hsin C Chiang1, Kevin R Kozak2, Glen S Kwon1,3. 1. a Pharmaceutical Sciences Division, School of Pharmacy , University of Wisconsin , Madison , USA. 2. b Mercy Regional Cancer Center Radiation Oncology , Janesville , Wisconsin , USA. 3. c Faculty of Pharmacy , King Abdulaziz , Jeddah , Saudi Arabia.
Abstract
PURPOSE: The aim of tumor-specific chemoradiotherapy is to achieve synergistic anticancer effects with clinically acceptable toxicity. Our previous studies showed that Pluronic P85 augments radiation cancer cell killing of (±)-gossypol in vitro. In this study, the radiosensitizing effect of (-)-gossypol, more potent Bcl protein inhibitor, with Pluronic P85 was investigated. MATERIALS AND METHODS: The inhibitory effect of (-)-gossypol solubilized Pluronic P85 with 0-8 Gy of radiation on clonogenic survival rate of A549 human lung adenocarcinoma cells was investigated in vitro. The anticancer effect of (-)-gossypol-solubilized Pluronic P85 with fractionated radiation of 15 Gy was assessed by A549 tumor-bearing mice. RESULTS: (-)-Gossypol-loaded Pluronic P85 was found to be a more potent radiosensitizer in vitro. Pluronic P85 increased the anti-proliferative activity of (-)-gossypol against A549 cells (82 ± 42 versus 190 ± 60 nM). In addition, the combination of P85 and (-)-gossypol effectively reduced clonogenic survival of A549 cells: (11 ± 5%) compared to (-)-gossypol and P85 alone (62 ± 27% and 93 ± 13%, respectively), and enhanced radiation cancer cell killing. In vivo, P85 (200 mg/kg/day) and (-)-gossypol (15 mg/kg/day) could be safely injected intravenously over 5 days and enhanced radiation-related tumor control in an A549 xenograft model. CONCLUSION: Pluronic P85 and (-)-gossypol act as a novel dual agent radiosensitizer and holds promise as a chemoradiotherapeutic strategy.
PURPOSE: The aim of tumor-specific chemoradiotherapy is to achieve synergistic anticancer effects with clinically acceptable toxicity. Our previous studies showed that Pluronic P85 augments radiation cancer cell killing of (±)-gossypol in vitro. In this study, the radiosensitizing effect of (-)-gossypol, more potent Bcl protein inhibitor, with Pluronic P85 was investigated. MATERIALS AND METHODS: The inhibitory effect of (-)-gossypol solubilized Pluronic P85 with 0-8 Gy of radiation on clonogenic survival rate of A549humanlung adenocarcinoma cells was investigated in vitro. The anticancer effect of (-)-gossypol-solubilized Pluronic P85 with fractionated radiation of 15 Gy was assessed by A549 tumor-bearing mice. RESULTS:(-)-Gossypol-loaded Pluronic P85 was found to be a more potent radiosensitizer in vitro. Pluronic P85 increased the anti-proliferative activity of (-)-gossypol against A549 cells (82 ± 42 versus 190 ± 60 nM). In addition, the combination of P85 and (-)-gossypol effectively reduced clonogenic survival of A549 cells: (11 ± 5%) compared to (-)-gossypol and P85 alone (62 ± 27% and 93 ± 13%, respectively), and enhanced radiation cancer cell killing. In vivo, P85 (200 mg/kg/day) and (-)-gossypol (15 mg/kg/day) could be safely injected intravenously over 5 days and enhanced radiation-related tumor control in an A549 xenograft model. CONCLUSION:Pluronic P85 and (-)-gossypol act as a novel dual agent radiosensitizer and holds promise as a chemoradiotherapeutic strategy.
Authors: K Furuse; M Fukuoka; M Kawahara; H Nishikawa; Y Takada; S Kudoh; N Katagami; Y Ariyoshi Journal: J Clin Oncol Date: 1999-09 Impact factor: 44.544
Authors: G R Gunassekaran; D Kalpana Deepa Priya; R Gayathri; D Sakthisekaran Journal: Biochem Biophys Res Commun Date: 2011-07-13 Impact factor: 3.575
Authors: Elena V Batrakova; Shu Li; Valery Yu Alakhov; Donald W Miller; Alexander V Kabanov Journal: J Pharmacol Exp Ther Date: 2003-02 Impact factor: 4.030
Authors: Daria Yu Alakhova; Nataliya Y Rapoport; Elena V Batrakova; Alexander A Timoshin; Shu Li; David Nicholls; Valery Yu Alakhov; Alexander V Kabanov Journal: J Control Release Date: 2009-10-06 Impact factor: 9.776
Authors: Paul A Townsend; Maria V Kozhevnikova; Olivier N F Cexus; Andrey A Zamyatnin; Surinder M Soond Journal: J Exp Clin Cancer Res Date: 2021-11-09