Cisplatin is the first platinum drug approved globally and has been used as a drug for cancer chemotherapy for more than 30 years [
1]. Cytostatic property of cisplatin was discovered by Barnett Rosenberg in the late 1960s when he observed anti-proliferative effect of platinum electrodes on bacterial suspension. Cisplatin has gained clinical success and has been proven to target various kinds of cancers, namely, lung, head and neck, bladder, cervical, and ovarian cancers [
2].
Upon cisplatin entry to the cell, it becomes activated by hydrolysis. Chloride ions are displaced by water molecules resulting in a strong positive electrophile that covalently binds to any nucleophile such as nitrogen in purine residues. The most reported reaction is the 1,2-intrastrand cross-linkage of the activated cisplatin with the purine residues at nitrogen (N7) which was demonstrated in vitro in DNA of cisplatin-treated salmon sperm cells. These results were further approved in another in vivo experiment that analyzed white blood cells of cancer patients [
15,
16]. Cisplatin causes damage in the DNA leading to p53 (tumor suppressor gene) activation. Meanwhile, damaged DNA is subjected to repair via p21 mediated cell cycle arrest. When the damaged DNA is not repairable, p53 induces apoptosis by inhibition of Bcl2 and consequent caspase activation [
17]. The main mechanism of cisplatin-induced cancer cell death is via apoptosis. Apoptosis is a procedure of programmed cell death, and is generally manifested by distinct morphological changes to the cell, e.g. cell shrinkage, chromatin condensation, plasma membrane “budding”, exposure of phosphatidyl serine at the cell surface, and caspase activation [
18]. The stimulation of a family of cysteines, otherwise known as caspases, is a critical step during the beginning stages of apoptosis. Caspases are characterized as either initiators or executioners of this cell death mechanism. The activation of caspases is dependent upon several stimuli, e.g. caspase-8 (initiator), activated by plasma membrane death receptors (DR), and caspase-9 (initiator), associated with mitochondrial collapse, resulting in caspase-3 and -7 (executioners) activation [
19]. Executioner caspases are responsible for many of the biochemical activities contributing towards the induction of apoptosis. This includes poly (ADP-ribose) polymerase (PARP) cleavage and activation, which leads to DNA fragmentation. Apoptosis is carried out by two major pathways known as the extrinsic and intrinsic pathways [
20]. The extrinsic pathway begins when ligands bind to tumor necrosis factor-α (TNFα) receptor family leading to the enrollment of procaspase-8 by adaptor molecules, resulting in the development of death-inducing signaling complex (DISC) [
21]. However, the intrinsic pathway commences when the cell undergo stress such as DNA damage, which subsequently leads to mitochondrial cytochrome c release and interaction with activating factor-1 (APAF-1), to form an active apoptosome structure, which thereby activates procaspase 9. In response, and in order to regulate DNA damage induced by apoptosis, Bcl-2 family proteins are regulated and undergo several modulations via controlling the release of cytochrome c. Therefore, genotoxic stress induced by cisplatin can result in the activation of several signal transduction pathways, contributing towards the induction of apoptosis.