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58.Praziquantel Synergistically Enhances Paclitaxel Efficacy to Inhibit Cancer Cell Growth 吡喹酮增强紫杉醇疗效协同抑制癌细胞的生长

PLOS ONE 2012 《公共科学图书馆•综合2012》

Abstract摘要

The major challenges we are facing in cancer therapy with paclitaxel (PTX) are the drug resistance and severe side effects. Massive efforts have been made to overcome these clinical challenges by combining PTX with other drugs. In this study, we reported the first preclinical data that praziquantel (PZQ), an anti-parasite agent, could greatly enhance the anticancer efficacy of PTX in various cancer cell lines, including PTX-resistant cell lines. Based on the combination index value, we demonstrated that PZQ synergistically enhanced PTX-induced cell growth inhibition. The co-treatment of PZQ and PTX also induced significant mitotic arrest and activated the apoptotic cascade. Moreover, PZQ combined with PTX resulted in a more pronounced inhibition of tumor growth compared with either drug alone in a mouse xenograft model. We tried to investigate the possible mechanisms of this synergistic efficacy induced by PZQ and PTX, and we found that the cotreatment of the two drugs could markedly decrease expression of X-linked inhibitor of apoptosis protein (XIAP), an antiapoptotic protein. Our data further demonstrated that down-regulation of XIAP was required for the synergistic interaction between PZQ and PTX. Together, this study suggested that the combination of PZQ and PTX may represent a novel and effective anticancer strategy for optimizing PTX therapy.我们面临的主要挑战是用紫杉醇(PTX) 治疗癌症时的抗药性和严重的副作用。大量努力用在克服这些临床挑战，通过将PTX与其他药物结合。在这项研究中，我们首先报道了吡喹酮的临床前数据(PZQ)，一种抗寄生虫药，可以大大增强PTX在各种癌症细胞系，包括PTX-resistant细胞系中的抗癌疗效。基于组合索引值，我们证明了PZQ协同增强PTX-induced细胞生长抑制。PZQ和PTX的联合治疗也诱导了显著的有丝分裂阻滞和激活凋亡级联。此外，PZQ与PTX结合会导致更加明显地抑制肿瘤的生长相比在鼠移植瘤模型中的其它单独用药。我们试图调查PZQ和PTX引起的协同疗效的可能机制，同时我们发现这两种药物的联合治疗可以显著减少凋亡蛋白(XIAP)中伴X染色体的抑制的表达，一种抗凋亡蛋白。我们的数据进一步表明，XIAP下调变化是PZQ和PTX间协同互用之所需。总之，本研究表明PZQ和PTX的组合可能会呈现一种新颖有效的抗癌策略从而优化PTX治疗。

bined Delivery of Paclitaxel and Tanespimycin via Micellar Nanocarriers: Pharmacokinetics, Efficacy and Metabolomic Analysis通过微胞载体结合传送紫杉醇和坦螺旋霉素:药物动力学、疗效和代谢物组学分析。

PLOS ONE 2013 《公共科学图书馆•综合2013》

Abstract摘要

Background: Despite the promising anticancer efficacy observed in preclinical studies, paclitaxel and tanespimycin (17- AAG) combination therapy has yielded meager responses in a phase I clinical trial. One serious problem associated with paclitaxel/17-AAG combination therapy is the employment of large quantities of toxic organic surfactants and solvents for drug solubilization. The goal of this study was to evaluate a micellar formulation for the concurrent delivery of paclitaxel and 17-AAG in vivo. Methodology/Principal Findings: Paclitaxel/17-AAG-loaded micelles were assessed in mice bearing human ovarian tumor xenografts. Compared with the free drugs at equivalent doses, intravenous administration of paclitaxel/17-AAG-loaded micelles led to 3.5- and 1.7-fold increase in the tumor concentrations of paclitaxel and 17-AAG, respectively, without significant altering drug levels in normal organs. The enhanced tumor accumulation of the micellar drugs was further confirmed by the whole-body near infrared imaging using indocyanine green-labeled micelles. Subsequently, the anticancer efficacy of paclitaxel/17-AAG-loaded micelles was examined in comparison with the free drugs (weekly 20 mg/kg paclitaxel, twice-weekly 37.5 mg/kg 17-AAG). We found that paclitaxel/17-AAG-loaded micelles caused near-complete arrest of tumor growth, whereas the free drug-treated tumors experienced rapid growth shortly after the 3-week treatment period ended. Furthermore, comparative metabolomic profiling by proton nuclear magnetic resonance revealed significant decrease in glucose, lactate and alanine with simultaneous increase in glutamine, glutamate, aspartate, choline, creatine and acetate levels in the tumors of mice treated with paclitaxel/17-AAG-loaded micelles. Conclusions/Significance: We have demonstrated in the current wok a safe and efficacious nano-sized formulation for the combined delivery of paclitaxel and 17-AAG, and uncovered unique metabolomic signatures in the tumor that correlate with the favorable therapeutic response to paclitaxel/17-AAG combination therapy.