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Is GSH Chelated Pt Molecule Inactive in Anti-Cancer Treatment? A Case Study of Pt6 GS4
Chunyu Zhang1, Liang Gao1, Qing Yuan1
1Department of Chemistry and Chemical Engineering, Beijing University of Technology, Beijing, 100124, P. R. China.
Abstract:
Platinum (Pt) drugs are widely used in anti-cancer treatment although many reports advocated that tumor cells could inactivate Pt drugs via glutathione-Pt (GSH-Pt) adducts formation. To date, GSH chelated Pt molecules have not been assessed in cancer treatment because GSH-Pt adducts are not capable of killing cancer cells, which is widely accepted and well followed. In this report, endogenous biothiol is utilized to precisely synthesize a GSH chelated Pt molecule (Pt6 GS4 ). This Pt6 GS4 molecule can be well taken up by aggressive triple negative breast cancer (TNBC) cells. Subsequently, its metabolites could enter nuclei to interact with DNA, finally the DNA-Pt complex triggers TNBC cell apoptosis via the p53 pathway. Impressively, high efficacy for anti-cancer treatment is achieved by Pt6 GS4 both in vitro and in vivo when compared with traditional first-line carboplatin in the same dosage. Compared with carboplatin, Pt6 GS4 keeps tumor bearing mice alive for a longer time and is non-toxic for the liver and kidneys. This work opens a route to explore polynuclear Pt compound with accurate architecture for enhancing therapeutic effects and reducing systemic toxicity.
Insights
A novel platinum compound, Pt6GS4, effectively targets triple-negative breast cancer cells by interacting with DNA and triggering apoptosis. This new platinum drug shows higher efficacy and lower toxicity than carboplatin in preclinical studies.
Area of Science:
- Oncology
- Medicinal Chemistry
- Nanotechnology
Background:
- Platinum-based chemotherapy is vital for cancer treatment but faces resistance due to glutathione inactivation.
- Glutathione-chelating platinum molecules have been overlooked due to the assumption that they cannot kill cancer cells.
Purpose of the Study:
- To synthesize and evaluate a novel glutathione-chelating platinum molecule, Pt6GS4, for anti-cancer therapy.
- To investigate the efficacy and toxicity of Pt6GS4 against triple-negative breast cancer (TNBC).
Main Methods:
- Precisely synthesized a novel glutathione-chelating platinum molecule (Pt6GS4) using endogenous biothiol.
- Assessed the uptake, DNA interaction, and apoptosis-inducing mechanism of Pt6GS4 in TNBC cells.
- Evaluated the in vitro and in vivo anti-cancer efficacy and systemic toxicity of Pt6GS4 compared to carboplatin.
Main Results:
- Pt6GS4 was effectively taken up by aggressive TNBC cells.
- Pt6GS4 metabolites entered cell nuclei, interacted with DNA, and triggered apoptosis via the p53 pathway.
- Pt6GS4 demonstrated superior anti-cancer efficacy and prolonged survival in tumor-bearing mice compared to carboplatin, with no observed liver or kidney toxicity.
Conclusions:
- The synthesized Pt6GS4 molecule offers a promising new strategy for enhancing platinum-based cancer therapy.
- This polynuclear platinum compound exhibits high therapeutic efficacy and reduced systemic toxicity, opening avenues for novel cancer drug development.
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