In the brain and spinal cord, glioma is the most common type of solid brain tumor with a five-year survival rate of only 5% and is the fourth leading cause of cancer deaths in the United States of America [1]. Glioblastoma multiforme (GBM) is the most proliferative type of tumor in the adult brain, and it is also brought on by overstimulating glial cells in the central nervous system [2]. Body cells like oligodendrocytes and microglia glia produce excessive oxidative stress during physiological and pathological processes such as oxidative stress, inflammation, and glutathione depletion [[3], [4], [5]]. The excessive Ca2+ influx-induced oxidative stress induces ADP-ribose (ADPR) production via the induction of DNA damage [6]. Pathways implicated in excessive Ca2+ influx-mediated DNA damage responses are typically aberrant in GBMs [7,8]. Through the promotion of excessive oxidative stress and Ca2+ influx, DNA damaging medicines, such as cisplatin (CiSP), are among the most successful medications available to clinicians for treating GBM tumors [[9], [10], [11]]. However, this efficacy is at the expense of considerable dose-limiting side effects [12]. The resistance of CiSP also induces high dose administration in patients with GBM [9]. Treatment of CiSP causes excessive production of cytosolic (cytROS), mitochondrial free reactive oxygen species (mitSOX), and Ca2+ influx in Denver Brain Tumor Research Group 05 MG (DBTRG-05MG) glioblastoma cells, which leads to apoptosis and cell death [9,10]. Nanoparticle developments could lead to the production of more potent and non-toxic tumor therapies [15].

Due to their potential antitumor effect, which has been shown by several in vitro studies, silver nanoparticles (AgNPs) are particularly intriguing for cancer therapy [15]. It has been shown that AgNPs may hinder cancer cell homeostasis by triggering increases in cytROS and mitSOX, which correspond to decreased proliferation rates as well as cellular oxidative damage and cell death [16,17]. Moreover, AgNPs may also disrupt important cancer hallmarks via the increase of cytosolic free Ca2+ concentration ([Ca2+]i) and caspase activation mediated-apoptosis level [[18], [19]]. Recently, it was reported that the treatment of AgNPs induced synergic action against CiSP-resistant several tumor cell line such as ovarian cancer [15,20], human prostate cancer (PC-3) [21], and colon cancer cell lines [22] via the activation of caspase −3 (CASP/3), caspase −8 (CASP/8), and caspase −9 (CASP/9). It was also noted that the treatment of CiSP upregulated mitSOX production, [Ca2+]i, and caspase activations (CASP/3, CASP/8, and CASP/9) in the DBTRG-05MG cells [11,13,14]. AgNPs and CiSP may operate synergistically to inhibit DBTRG-05MG because of their distinct effects on the control of Ca2+ signaling and apoptosis.

In both healthy and cancerous cells, activating cation channels results in an increase in [Ca2+]i concentration. Changes in [Ca2+]iconcentrations affect many signaling pathways, including cell migration and apoptosis [23]. The transient receptor potential (TRP) superfamily of cation channels is a subfamily of Ca2+ permeable cation channels. In mammalian cells, the superfamily has 28 members, and TRP melastatin 2 (TRPM2) is one of them [6]. In the nucleus, DNA damage results in the production of ADPR [19]. ADPR and oxidative stress both activate TRPM2 [[24], [25], [26]]. In addition, the activation of TRP channels increased caspase activities and apoptosis levels in several cancer cell lines [22,23]. The anticancer actions of chemotherapeutic agents such as CiSP and paclitaxel were also increased via the stimulation of TRPM2 in the DBTRG-05MG glioblastoma and human laryngeal squamous cancer death [11,23]. Hence, TRPM2 channels serve as targets of therapeutic agents to decrease tumor growth and increase tumor death in cancer treatments [5,26], and the oxidant can potentiate the anticancer action of CiSP in the DBTRG-05MG cells.

Current literature data highlight AgNPs' potential as a desirable candidate for the creation of anticancer medications and treatments. We propose that synergetic AgNP toxicity may be advantageous for augmenting conventional popular antineoplastic drug (CiSP) therapy. To identify the molecular processes brought on by combined AgNPs/CiSP exposure in a DBTRG-05MG cell line, we used a laser scan confocal microscope (CLSM-800), patch-clamp, plate reader, and spectrophotometer-based TRPM2 channel activation, apoptosis level, and oxidative stress concentration investigations.