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Novel Mitochondria-Based Targeting Restores Responsiveness in Therapeutically Resistant Human Lung Cancer Cells.

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机构： [1]Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [2]Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California. [3]VA Greater Los Angeles Healthcare System, Los Angeles, California. [4]Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California. [5]Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.

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Cisplatin and tyrosine kinase inhibitors (TKI) are recommended to treat non-small cell lung cancer (NSCLC). However, ubiquitously acquired drug resistance in patients with NSCLC diminishes their therapeutic efficacy. Strategies for overcoming cisplatin and TKI resistance are an unmet medical need. We previously described a group of near-infrared heptamethine carbocyanine fluorescent dyes, referred to as DZ, with tumor-homing properties via differentially expressed organic anion-transporting polypeptides on cancer cells. This group of organic dyes can deliver therapeutic payloads specifically to tumor cells in the form of a chemical conjugate. We synthesized DZ-simvastatin (DZ-SIM) initially to target cholesterol biosynthesis in lung cancer cells. DZ-SIM killed both cisplatin-sensitive and cisplatin-resistant as well as EGFR-TKI-sensitive and EGFR-TKI-resistant lung cancer cells. This conjugate specifically accumulated in and effectively inhibited the growth of xenograft tumors formed by NSCLC cells resistant to first-generation (H1650) and third-generation (PC9AR) EGFR TKIs. DZ-SIM induced cell death by targeting mitochondrial structure and function. We concluded that DZ-SIM could be a promising novel therapy for overcoming drug resistance in patients with NSCLC.©2021 American Association for Cancer Research.

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大类 | 2 区医学

小类 | 2 区肿瘤学

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大类 | 2 区医学

小类 | 2 区肿瘤学

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第一作者机构： [1]Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China. [2]Samuel Oschin Comprehensive Cancer Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.

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