1. A hydroxychloroquine platinum(IV) conjugate displaying potent antimetastatic activities by suppressing autophagy to improve the tumor microenvironment.
- Author
-
Li L, Chen Y, Zhang M, Li S, Feng S, He YQ, Zhang N, Liu Z, Liu M, and Wang Q
- Subjects
- Animals, Mice, Humans, Cell Proliferation drug effects, Cell Line, Tumor, Female, Platinum chemistry, Platinum pharmacology, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Lung Neoplasms metabolism, Coordination Complexes pharmacology, Coordination Complexes chemistry, Mice, Inbred BALB C, Drug Screening Assays, Antitumor, Apoptosis drug effects, Hydroxychloroquine pharmacology, Hydroxychloroquine chemistry, Autophagy drug effects, Tumor Microenvironment drug effects, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry
- Abstract
Protective autophagy is a promising target for antitumor drug exploration. A hydroxychloroquine (HCQ) platinum(IV) complex with autophagy suppressing potency was developed, which displayed potent antitumor activities with a TGI rate of 44.2% against 4T1 tumors in vivo and exhibited a rather lower toxicity than cisplatin. Notably, it exhibited satisfactory antimetastatic activities toward lung pulmonary metastasis models with an inhibition rate of 49.6% and was obviously more potent than CDDP, which has an inhibition rate of 21.6%. Mechanism detection revealed that it caused serious DNA damage and upregulated the expression of γ-H2AX and p53. More importantly, the incorporation of an autophagy inhibitor HCQ endowed the platinum(IV) complex with potent autophagy impairing properties by perturbing the lysosomal function in tumor cells, which promoted apoptosis synergistically with DNA injury. Then, the impaired autophagy further led to the suppression of hypoxia and inflammation in the tumor microenvironment by downregulating ERK1/2, HIF-1α, iNOS, caspase1 and COX-2. Adaptive immune response was improved by inhibiting the immune checkpoint PD-L1 and further increasing CD4
+ and CD8+ T cells in tumors. Then, tumor metastasis was effectively inhibited by restraining angiogenesis through inhibiting VEGFA, MMP-9, and CD34.- Published
- 2024
- Full Text
- View/download PDF