Elucidating the Dual Mechanistic Action and Synergism of Platinum Complexes bearing Valproic Acid as Leaving Ligand on NF-κB and Inflammatory Pathways in Glioma

Abstract

The Valproic acid (VPA), an anti-epileptic drug, has demonstrated anticancer properties alone or in combination regimens in glioma. It has been shown synergistic activity with cisplatin in resistant cancer cells. In the current study, we synthesized Pt (II) complexes bearing VPA as ancillary/leaving ligand. All these complexes were obtained in good yields through simple reproducible synthetic procedures and characterized by multiple analytical techniques in both solution and solid state. In situ release of ancillary ligand (VPA) by these complexes was studied by ¹H NMR in solution state that was catalysed by water in time dependent manner. The tumour preferential selective VPA-Pt actively controlling NF-kB signaling, culminating in the attenuation of IL-6 expression and the concomitant activation of p53 and caspase-3 pathways in gliomas. VPA-Pt exhibits potent cytotoxicity in human and mice glioma cancer cell lines, inducing apoptosis as evidenced by inhibition of cell proliferation and migration, disruption of mitochondrial membrane potential, and suppression of colony formation. An inhibitory effect of VPA-Pt4 on glioma was clearly evidenced through in vivo live bioluminescence imaging, histopathological examination, immunofluorescence evaluation, and protein expression analysis demonstrated that VPA-Pt4 significantly triggered apoptosis, with elevated levels of P53, caspase-3, cleaved caspase-3, along with a reduction in IL-6. Our discovery reveals a novel and efficient approach to glioma therapy.