A hydroxychloroquine platinum(IV) conjugate displaying potent antimetastatic activities by suppressing autophagy to improve the tumor microenvironment

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Autophagy plays a dual role in cancer, acting as a protective mechanism that can be targeted for antitumor drug development.
• Platinum-based chemotherapy agents like cisplatin are effective but often accompanied by significant toxicity.
• Developing novel platinum complexes with enhanced efficacy and reduced side effects is a critical area of cancer research.

Purpose of the Study:

• To develop and evaluate a novel platinum(IV) complex incorporating hydroxychloroquine (HCQ) with potent autophagy-suppressing and antitumor activities.
• To investigate the antimetastatic potential and underlying mechanisms of the novel HCQ-platinum(IV) complex.
• To assess the complex's effects on the tumor microenvironment and adaptive immune response.

Main Methods:

• Synthesis and characterization of a hydroxychloroquine (HCQ) platinum(IV) complex.
• In vivo evaluation of antitumor activity against 4T1 tumors and antimetastatic activity in lung metastasis models.
• Assessment of DNA damage, apoptosis, and autophagy impairment in tumor cells.
• Analysis of tumor microenvironment modulation, including hypoxia, inflammation, and immune cell infiltration.
• Evaluation of angiogenesis inhibition markers.

Main Results:

• The HCQ-platinum(IV) complex demonstrated significant antitumor activity (44.2% TGI) and antimetastatic efficacy (49.6% inhibition) with lower toxicity than cisplatin.
• The complex induced DNA damage, upregulated DNA repair markers (γ-H2AX, p53), and impaired lysosomal function, leading to synergistic apoptosis.
• It suppressed tumor hypoxia and inflammation by downregulating key mediators (ERK1/2, HIF-1α, iNOS, caspase1, COX-2) and enhanced adaptive immunity by inhibiting PD-L1 and increasing CD4+/CD8+ T cells.
• Angiogenesis was effectively inhibited by targeting VEGFA, MMP-9, and CD34.

Conclusions:

• The novel HCQ-platinum(IV) complex is a potent antitumor and antimetastatic agent with a promising mechanism of action involving autophagy suppression and tumor microenvironment modulation.
• This complex represents a potential therapeutic strategy with improved efficacy and reduced toxicity compared to traditional platinum drugs.
• Targeting autophagy in combination with platinum chemotherapy offers a viable approach for overcoming drug resistance and improving cancer treatment outcomes.