Tomoda Keishiro, Chiang Hsin C, Kozak Kevin R, Kwon Glen S
a Pharmaceutical Sciences Division, School of Pharmacy , University of Wisconsin , Madison , USA.
b Mercy Regional Cancer Center Radiation Oncology , Janesville , Wisconsin , USA.
Int J Radiat Biol. 2017 Apr;93(4):402-406. doi: 10.1080/09553002.2016.1257833. Epub 2016 Dec 9.
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.
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.
(-)-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.
Pluronic P85 and (-)-gossypol act as a novel dual agent radiosensitizer and holds promise as a chemoradiotherapeutic strategy.
肿瘤特异性放化疗的目的是在临床可接受的毒性下实现协同抗癌效果。我们之前的研究表明，普朗尼克P85在体外可增强（±）-棉酚对癌细胞的杀伤作用。在本研究中，研究了更有效的Bcl蛋白抑制剂（-）-棉酚与普朗尼克P85的放射增敏作用。
体外研究了用普朗尼克P85溶解的（-）-棉酚在0-8 Gy辐射下对A549人肺腺癌细胞克隆形成存活率的抑制作用。通过荷A549肿瘤小鼠评估了用普朗尼克P85溶解的（-）-棉酚与15 Gy分次放疗的抗癌效果。
发现负载（-）-棉酚 的普朗尼克P85在体外是一种更有效的放射增敏剂。普朗尼克P85增加了（-）-棉酚对A549细胞的抗增殖活性（82±42对190±60 nM）。此外，P85与（-）-棉酚的组合有效降低了A549细胞的克隆形成存活率：（11±5%），相比单独使用（-）-棉酚和P85（分别为62±27%和93±13%），并增强了对癌细胞的辐射杀伤作用。在体内，P85（200 mg/kg/天）和（-）-棉酚（15 mg/kg/天）可以在5天内安全地静脉注射，并在A549异种移植模型中增强了与放疗相关的肿瘤控制。
普朗尼克P85和（-）-棉酚作为一种新型的双药放射增敏剂，有望成为一种放化疗策略。
