Gliomas, including glioblastomas, rank among the most prevalent and aggressive types of brain tumors [1]. Despite extensive clinical trials and intensive available therapy, the prognosis sustains unfavourable [2,3]. There is an immediate need to advance innovative therapeutic modalities for these patients, as the existing standard of care has remained static for over a decade [4]. Nuclear factor kappa-B (NF-κB) serves as a critical nuclear transcription factor that mediates inflammatory responses, and sustained activation within a chronically inflammatory microenvironment milieu can drive tumorigenesis [5]. Glioma pathogenesis, characterized by intricate molecular mechanisms, is associated with chronic NF-κB activation that exacerbates cancer aggressiveness by modulating inflammatory cytokines like IL-6, thereby facilitating tumor progression and promoting malignancy [6,7], while NF-κB and p53 generally function in a reciprocal manner in cancer cells, with p53 activity being linked to the induction of apoptosis cell death, whereas NF-κB signaling confers resistance to apoptotic stimuli [8]. It has been shown that the regulatory control of p53 is contingent upon an intact NF-κB site in its promoter region, with NF-κB induction via TNFα stimulation or transient expression of its p65 subunit, enabling p53 expression [9]. Caspase 3 is responsible for nuclear modifications in apoptosis, and it is considered the key effector caspase [10], while cleaved Caspase-3 responsible for morphological and biochemical changes in apoptosis [11]. Emerging evidence indicates an important contribution of caspases as mediators or regulators of nuclear factor-κB (NF-κB) signaling, which plays a key role in inflammation and immunity [12]. It has been reported that caspase-3 activation or overexpression leads to a significant reduction in various cytokine signaling pathways by proteolytically cleaving NF-κB subunits such as p65/RelA, RelB, and c-Rel. Notably, mutants of p65/RelA, RelB, or c-Rel that are resistant to caspase-3 can largely reverse the suppression of cytokine production induced by caspase-3 [13].

Temozolomide (TMZ) remains the primary chemotherapeutic agent administered in glioma; however, both intrinsic and acquired resistance to TMZ undermine the limited efficacy of this drug. Since the approval of TMZ, platinum-based drugs have typically been limited to instances of tumor progression and recurrence [14,15]. To circumvent the current treatment strategies in glioma treatment, an extensive array of classical and non-classical platinum complexes has been synthesized and subjected to rigorous assessment for their anticancer activity [16,17]. Platinum-based drugs are employed in the clinical treatment of gliomas; however, the development of drug resistance severely compromise the therapeutic effectiveness, thereby deters their clinical application [[18], [19], [20], [21]]. Developing metal-based drugs with a mechanism of action distinct to classical platinum (II) drugs is an area being extensively explored [22]. Brabec et al. results indicated that structural perturbations in DNA instigated by platinum(II) complexes are intricately associated with their augmented efficiency in impending the binding of NF-κB proteins to their κB sites, thereby implying their cytotoxic potential [23].

Concerning glioma, it has been demonstrated that HDAC functions are also disrupted, contributing to the aberrant activation of various signaling pathways [24]. Thus, considerable interest in the treatment of glioma using HDAC inhibitors (HDACi) has been provoked. Two of the most potent HDACi against gliomas are valproic acid (VPA, 2-propyl-pentanoic acid) and sodium butyrate (NaBt) [25,26]. Valproic acid is under investigational preparation for glioma treatment [27]. In the pursuit of accelerating drug discovery through the repurposing of established existing drugs, valproic acid emerges as a promising candidate [28]. Administration in combination with radiotherapy or chemotherapy, VPA has the capacity to impede the development of glioma resistance to chemotherapy or radiotherapy modalities [29,30]. Valproic acid has been found to exert inhibitory effects on glioma in both in vitro and in vivo, either as a standalone treatment or synergistically [31,32]. Notably, Several HDACi have been showed to cross the blood-brain barrier (BBB) effectively and exhibit substantial anti-cancer activity, whether used as monotherapy or in combination with other cytotoxic agents [33]. Wei zhao et al. elucidated that administration of valproic acid significantly improved BBB integrity in an intracerebral hemorrhage (ICH) model, which was concomitant with a decrease in p-NFκB activity, as well as reduced level of IL-6, MMP9 and TNFα [34,35]. Further findings by lucke et al. substantiate that VPA can traversing the BBB unimpeded [36]. Research conducted by Chi Zhang et al. showed that VPA induces apoptosis in U87 glioma cells in a dose dependent manner through the mitochondria mediated pathway in vitro [37]. Ching-Tai Lin et al. revealed that VPA not only exhibits synergistic cytotoxicity effects with cisplatin across various ovarian carcinoma cell lines but also re-sensitizes the cells that showed acquired cisplatin resistance [38]. In recent studies regarded as chemosensitizers, the addition of well-tolerated doses of VPA to platinum-based chemotherapeutics has established efficacy in both in vitro and in vivo models across multiple cancer types and progression cancer stages [39]. The pioneering work of Darren M Griffith et al. presented the first platinum-VPA complexes, specifically trans-[Pt(VPA-1H)2(NH3)(py)] and trans-[Pt(VPA-1H)2(py)2] (py = pyridine) wherein VPA ligands substituted chloride group in trans-[PtCl2(py)2] and trans-[PtCl2(NH3)(py)]. These VPA-platinum exhibited superior cytotoxicity against both cisplatin-sensitive A2780 and cisplatin resistant A2780cisR ovarian cell lines compared to conventional cisplatin [40].

Here, we prepared eight platinum complexes bearing valproic acid as biologically compatible leaving ligand. All these complexes were characterized in solution or solid state by detailed analytical methods. Ancillary ligand (VPA) release by these complexes was monitored in solution state by 1H NMR spectroscopy. All these complexes were evaluated for their cytotoxicity effect in glioma cells. We examine the effects of platinum-valproic acid complexes, with a particular focus on the modulation of the interconnected NF-κB, IL-6, p53 and Caspase-3 pathways in glioma cells. By employing an integrative approach that widths both cellular and preclinical models, this research seeks to explicate how these complexes impact NF-κB activity and interfere with the IL-6, p53 and caspase-3 feedback loops in glioma. Through comprehensive in vitro and in vivo analyses of cytokine expression, signaling pathway activation, and cellular responses. By targeting these interconnected pathways, we aim to disrupt the inflammatory and pro survival signals that contribute to glioma progression, ultimately flagging the way for the development of more effective therapeutic strategies that can expand patient outcomes in this challenging disease and will shed light on the mechanistic basis of the anticancer efficacy of platinum-valproic acid complexes.