Department of Biochemistry and Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA.
Neoplasia. 2013 May;15(5):523-34. doi: 10.1593/neo.13142.
Toxicity and chemoresistance are two major issues to hamper the success of current standard tumor chemotherapy. Combined therapy of agents with different mechanisms of action is a feasible and effective means to minimize the side effects and avoid the resistance to chemotherapeutic drugs while improving the antitumor effects. As the most essential tumor suppressor, p53 or its pathway has been an attractive target to develop a new type of molecule-targeting anticancer therapy. Recently, we identified a small molecule, Inauhzin (INZ), which can specifically activate p53 by inducing its deacetylation. In this study, we tested if combination with INZ could sensitize tumor cells to the current chemotherapeutic drugs, cisplatin (CIS) and doxorubicin (DOX). We found that compared with any single treatment, combination of lower doses of INZ and CIS or DOX significantly promoted apoptosis and cell growth inhibition in human non-small lung cancer and colon cancer cell lines in a p53-dependent fashion. This cooperative effect between INZ and CIS on tumor suppression was also confirmed in a xenograft tumor model. Therefore, this study suggests that specifically targeting the p53 pathway could enhance the sensitivity of cancer cells to chemotherapeutic agents and markedly reduce the doses of the chemotherapy, possibly decreasing its adverse side effects.
毒性和耐药性是阻碍当前肿瘤化疗标准成功的两个主要问题。联合使用具有不同作用机制的药物是一种可行且有效的方法，可以最大限度地减少副作用，避免对化疗药物的耐药性，同时提高抗肿瘤效果。作为最重要的肿瘤抑制因子，p53 或其通路一直是开发新型分子靶向抗癌治疗的有吸引力的靶点。最近，我们鉴定了一种小分子 Inauhzin（INZ），它可以通过诱导去乙酰化来特异性激活 p53。在这项研究中，我们测试了 INZ 联合是否可以使肿瘤细胞对当前的化疗药物顺铂（CIS）和多柔比星（DOX）敏感。我们发现，与任何单一治疗相比，INZ 与 CIS 或 DOX 的低剂量联合以 p53 依赖性方式显著促进了人非小细胞肺癌和结肠癌细胞系的细胞凋亡和生长抑制。这种 INZ 和 CIS 在肿瘤抑制方面的协同作用也在异种移植肿瘤模型中得到了证实。因此，这项研究表明，特异性靶向 p53 通路可以增强癌细胞对化疗药物的敏感性，并显著降低化疗药物的剂量，可能减少其不良反应。
