Improving chemotherapy by releasing platinum agents from endolysosomes

Chemotherapeutics remain widely used for the treatment of cancer, and the majority act by causing DNA damage in cancer cells. Many of these are hydrophobic and are taken up by cancer cells through a process called endocytosis. However, such chemotherapeutics may be limited as they are retained in the lysosomes and fail to reach the DNA in the nucleus. Widely-used chemotherapeutics such as bleomycin and gemcitabine are well-known to suffer from this limitation. Other chemotherapeutics such as oxaliplatin are suspected to be similarly limited, yet concrete evidence is lacking. The aim of this proposal is to (1) confirm that oxaliplatin localizes within the endo-lysosomes in cancer cells, and (2) that oxaliplatin can be released by selective destruction of the lysosomes.

化疗药物仍是当前癌症治疗的主流方案，其中绝大多数通过诱导癌细胞DNA损伤发挥抗肿瘤活性。此类药物多为疏水化合物，需经胞吞作用被癌细胞摄取。然而这类化疗药物存在显著局限：它们会被滞留在溶酶体中，无法抵达细胞核内的DNA靶点。临床常用的博来霉素（bleomycin）与吉西他滨（gemcitabine）均存在该类局限。另有奥沙利铂（oxaliplatin）等化疗药物被推测存在类似局限，但目前尚无确凿证据支持这一推测。本研究的核心目标为：（1）验证奥沙利铂在癌细胞内定位于内体-溶酶体区域；（2）证实可通过选择性破坏溶酶体实现奥沙利铂的释放。