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In Vitro and In Vivo Relevant Antineoplastic Activity of Platinum(II) Complexes toward Triple-Negative MDA-MB-231
Leide Laura Figueiredo Maciel1, Marina Barreto Silva1, Rafaela Oliveira Moreira2
1Laboratório de Biologia do Reconhecer, Universidade Estadual do Norte Fluminense Darcy Ribeiro, Campos dos Goytacazes 28013-602, RJ, Brazil.
Pharmaceutics
|October 27, 2022
Summary
New platinum complexes show potent antineoplastic activity. Complex 4 effectively targets cancer cells, including triple-negative breast cancer, while sparing healthy cells, and reduces tumor growth in vivo.
Area of Science:
- Inorganic Chemistry
- Medicinal Chemistry
- Cancer Biology
Background:
- Platinum(II) complexes are investigated for their antineoplastic properties.
- Development of novel platinum compounds with improved efficacy and selectivity is crucial for cancer therapy.
Purpose of the Study:
- To evaluate the in vitro and in vivo antineoplastic activity of two novel platinum(II) complexes, [Pt(HL3)Cl]·H2O (3) and [Pt(HL4)Cl]·H2O (4).
- To investigate the mechanism of action of the more potent complex (4) against MDA-MB-231 triple-negative breast cancer cells.
Main Methods:
- Cytotoxicity was assessed using MTT assay against various cancer cell lines (MDA-MB-231, MCF-7, A549, PC3, BXPC-3) and peripheral blood mononuclear cells (PBMC).
- Apoptosis induction was analyzed by Sub-G1 cell cycle analysis, mitochondrial membrane potential, reactive oxygen species (ROS) levels, and caspase activation.
- Ultrastructural changes were examined using scanning electron microscopy (SEM) and transmission electron microscopy (TEM).
- In vivo efficacy was evaluated in an MDA-MB-231 tumor xenograft murine model.
Main Results:
- Complex (4) exhibited higher cytotoxicity against all tested cancer cell lines and lower toxicity against human PBMC compared to complex (3).
- Complex (4) induced apoptosis in MDA-MB-231 cells via both extrinsic and intrinsic pathways, evidenced by DNA content loss, mitochondrial depolarization, increased ROS, and caspase activation.
- SEM and TEM revealed characteristic apoptotic morphological changes, including membrane blebbing and DNA fragmentation.
- Complex (4) significantly reduced tumor size in a murine xenograft model.
Conclusions:
- Complex (4) demonstrates significant in vitro and in vivo antineoplastic potential, particularly against triple-negative breast cancer.
- The cytotoxic mechanism involves the induction of apoptosis through multiple cellular pathways.
- Complex (4) represents a promising candidate for further development as a chemotherapeutic agent.
