[Pt(O,O′-acac)(γ-acac)(DMS)] Induces Autophagy in Caki-1 Renal Cancer Cells

Abstract

We have demonstrated the cytotoxic effects of [Pt(O,O′-acac)(γ-acac)(dimethyl sulfide (DMS))] on various immortalized cell lines, in primary cultures, and in murine xenograft models in vivo. Recently, we also showed that [Pt(O,O’-acac)(γ-acac)(DMS)] is able to kill Caki-1 renal cells both in vivo and in vitro. In the present paper, apoptotic and autophagic effects of [Pt(O,O′-acac)(γ-acac)(DMS)] and cisplatin were studied and compared using Caki-1 cancerous renal cells. The effects of cisplatin include activation of caspases, proteolysis of enzyme poly ADP ribose polymerase (PARP), control of apoptosis modulators B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and BH3-interacting domain death agonist (Bid), and cell cycle arrest in G2/M phase. Conversely, [Pt(O,O’-acac)(γ-acac)(DMS)] did not induce caspase activation, nor chromatin condensation or DNA fragmentation. The effects of [Pt(O,O’-acac)(γ-acac)(DMS)] include microtubule-associated proteins 1A/1B light chain 3B (LC3)-I to LC3-II conversion, Beclin-1 and Atg-3, -4, and -5 increase, Bcl-2 decrease, and monodansylcadaverine accumulation in autophagic vacuoles. [Pt(O,O’-acac)(γ-acac)(DMS)] also modulated various kinases involved in intracellular transduction regulating cell fate. [Pt(O,O’-acac)(γ-acac)(DMS)] inhibited the phosphorylation of mammalian target of rapmycin (mTOR), p70S6K, and AKT, and increased the phosphorylation of c-Jun N-terminal kinase (JNK1/2), a kinase activity pattern consistent with autophagy induction. In conclusion, while in past reports the high cytotoxicity of [Pt(O,O’-acac)(γ-acac)(DMS)] was always attributed to its ability to trigger an apoptotic process, in this paper we show that Caki-1 cells die as a result of the induction of a strong autophagic process.

Ruthenium Complexes as Promising Candidates against Lung Cancer

“…To the best of our knowledge, there are only a few studies on the inhibition of cell growth caused by metal complexes through autophagy induction. For instance, a Pt-based complex, [Pt(O,O’-acac)(γ-acac)(DMS)], induced autophagy in Caki-1 renal cancer cells [ 101 ] and rat B50 neuroblastoma [ 102 ]. Apart from Pt-based agents, Piccolo M et al [ 103 ] and Irace C et al [ 104 ] have certified that the activation of autophagic pathways is a common feature with Ru(III) complexes against breast cancer cells.…”

Autophagy as a Vital Therapy Target for Renal Cell Carcinoma

“…For example, Hongyan et al found that NVP-BEZ235, a novel dual PI3K/mTOR inhibitor, induced cell apoptosis and autophagy in RCC (H. Li et al, 2013 ). Furthermore, Antonaci et al indicated that dimethyl sulfide (DMS) induced autophagy in Caki-1 cells through PI3K/AKT/mTOR/p70S6K pathways ( Antonaci et al, 2019 ). Sunitinib blocking the Akt/mTOR/p70S6K pathway has resulted in autophagy activation in vivo and in vitro (M. L. Li et al, 2018 ).…”

NMR-Based Metabolomics in Metal-Based Drug Research

“…This complex is interesting for its higher anticancer activity, enhanced pharmacokinetics, bio-distribution, and tolerability showed in comparison to cisplatin. This is produced by a non-genomic mechanism of action, as previously demonstrated both in vitro and in vivo [77,78,79,80,81,82]. The observed higher cytotoxicity of Ptac2S with respect to cisplatin in the cisplatin-resistant SKOV-3 cells, evaluated by a preliminary MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, led us to investigate further the action mechanism of this complex, which is able to overcome cisplatin resistance.…”

“…Furthermore, the different lipidic profile in Ptac 2 S, with respect to cisplatin-treated cells, indicates a possible cell death mechanism different from apoptosis (the known cisplatin-induced mechanism of death) [81]. In this context, biological assays have recently demonstrated that Ptac2S induces autophagy in another cisplatin-resistant cancer cell line (Caki-1, a renal cancer cell line) [82]. These findings parallel the results derived through the NMR metabolomic analysis, confirming the power of the technique in the investigation of mechanisms of action.…”