Enhanced anticancer potency with reduced nephrotoxicity of newly synthesized platin-based complexes compared with cisplatin

Autor: Roya Salehi, Selda Abyar, Fatemeh Ramazani, Ali Akbar Khandar, Seyed Abolfazl Hosseini-Yazdi, Jonathan M. White, Mahdi Edalati, Houman Kahroba, Mehdi Talebi
Přispěvatelé: Toxicogenomics, RS: GROW - R1 - Prevention
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Scientific Reports, 12(1):8316. Nature Publishing Group
ISSN: 2045-2322
Popis: As a platinum-containing anticancer drug, cisplatin is the keystone for treating many malignancies. Nephrotoxicity is the main dose-limiting toxicity, and several hydration therapies and supplementary strategies are utilized to reduce cisplatin-induced kidney damage, so the discovery and development of effective and safe antitumor drugs are still on the path of human health. Herein, a new four-coordinated Pt complex [Pt(TSC)Cl] using N(4)-phenyl-2-formylpyridine thiosemicarbazone (HTSC) was synthesized and characterized by single-crystal X-ray diffraction, (HNMR)-H-1, FT-IR, LC/MS and CHN elemental analysis. The Pt(TSC)Cl complex revealed antiproliferative activity against A549, MCF-7 and Caco-2 cell lines with a low micromolar IC50 (200-1.75 mu M). Specifically, the Pt(TSC)Cl complex displayed more selectivity in Caco-2 cells (IC50 = 2.3 mu M) than cisplatin (IC50 = 107 mu M) after 48 h of treatment. Moreover, compared with cisplatin, a known nephrotoxic drug, the Pt(TSC)Cl complex exhibited lower nephrotoxicity against Hek293 normal cells. We also found that the Pt(TSC)Cl complex can effectively prevent cancer cell propagation in sub-G1 and S phases and induce apoptosis (more than 90%). Real time PCR and western analysis demonstrated that the expression pattern of apoptotic genes and proteins is according to the intrinsic apoptosis pathway through the Bax/Bcl-2-Casp9-Casp3/Casp7 axis. Collectively, our findings indicated that the Pt(TSC)Cl complex triggers apoptosis in Caco-2 cell lines, while low nephrotoxicity was shown and may be considered a useful anticancer drug candidate for colorectal cancers for further optimization and growth. The authors were financially supported by the National Institute for Medical Research Development (NIMAD) [Grant Number 964557] for the financial support of this research. The authors also highly appreciate Research Council University of Tabriz and University of Melbourne for X-ray crystallography.
Databáze: OpenAIRE
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