Complexes based on heavy metals have great potential for the treatment of a wide variety of cancers but their use is often limited due to toxic side effects. Here we describe the synthesis of two new cadmium complexes using N(4)-phenyl-2-formylpyridine thiosemicarbazone (L1) and 5-aminotetrazole (L2) as organic ligands and the evaluation of their anti-cancer and nephrotoxic potential in vitro. The complexes were characterized by Single-crystal X-ray data diffraction, 1HNMR, FT-IR, LC/MS spectrometry and CHN elemental analysis. Next, cytotoxicity of these cadmium complexes was evaluated in several cancer cell lines, including MCF-7 (breast), Caco-2 (colorectal) and cisplatin-resistant A549 (lung) cancer cell lines, as well as in conditionally-immortalized renal proximal tubule epithelial cell lines for evaluating nephrotoxicity compared to cisplatin. We found that both compounds were toxic to the cancer cell lines in a cell-cycle dependent manner and induced caspase-mediated apoptosis and caspase-independent cell death. Nephrotoxicity of these compounds was compared to cisplatin, a known nephrotoxic drug, in vitro. Our results demonstrate that compound {2}, but not compound {1}, exerts increased cytotoxicity in MCF-7 and A549 cell lines, combined with reduced nephrotoxic potential compared to cisplatin. Together these data make compound {2} a likely candidate for further development in cancer treatment.
Self-assembling molecular drugs combine the easy preparation typical of small-molecule chemotherapy and the tumour-targeting properties of drug–nanoparticle conjugates. However, they require a supramolecular interaction that survives the complex environment of a living animal. Here we report that the metallophilic interaction between cyclometalated palladium complexes generates supramolecular nanostructures in living mice that have a long circulation time (over 12 h) and efficient tumour accumulation rate (up to 10.2% of the injected dose per gram) in a skin melanoma tumour model. Green light activation leads to efficient tumour destruction due to the type I photodynamic effect generated by the self-assembled palladium complexes, as demonstrated in vitro by an up to 96-fold cytotoxicity increase upon irradiation. This work demonstrates that metallophilic interactions are well suited to generating stable supramolecular nanotherapeutics in vivo with exceptional tumour-targeting properties.
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, 1HNMR, 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 µM). Specifically, the Pt(TSC)Cl complex displayed more selectivity in Caco-2 cells (IC50 = 2.3 µM) than cisplatin (IC50 = 107 µM) 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.
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