Cisplatin, also called Cis-diamminedichloridoplatinum(II), is a platinum (Pt)-based compound widely used for cancer treatment. Its cytotoxic property was first found in the 1960s, when Rosenberg and colleagues at Michigan State University reported a surprising discovery that the electrolysis products from a platinum electrode suppressed E.coli cell division (Rosenberg, Van Camp, & Krigas, 1965). Cisplatin was later identified as the active component in the electrolysis products that inhibited cell division. Since then, much interest has been generated for its potential for cancer treatment. In 1968, cisplatin was first administrated intraperitoneally to mice and it remarkably suppressed tumor growth (sarcoma and leukemia). The successful test in animals was followed by clinical testing in human patients in early 1970s and the drug was approved by United States Food and Drug Administration (FDA) in 1978 (Kelland, 2007).

It has been well documented that cisplatin mainly functions as a DNA damaging agent to suppress tumor growth (reviewed in Jamieson & Lippard, 1999). Once administrated to patients, the first barrier for cisplatin is the entry into the cell. Studies suggest that cisplatin can passively cross the phospholipid bilayer of the cell membrane to reach its intracellular location (Martinho, Santos, Florindo, & Silva, 2019; Ruano, Cárdenas, & Nogueira, 2021), due to its small size and neutral charge. Another important mechanism for cisplatin uptake is through active transport by transmembrane transporters, such as the high-affinity copper transporter Ctr1 protein (Ishida, Lee, Thiele, & Herskowitz, 2002). In both yeast and mouse cells, knockout of the Ctr1 gene increased cellular resistance to cisplatin, due to decreased intracellular cisplatin accumulation (Ishida et al., 2002). Cisplatin is quickly activated once it enters the cell, through a series of aquation reactions, in which the chloride ligands of cisplatin are replaced by water molecules. The activated cisplatin is a potent electrophile that directly reacts with DNA, inducing cross-links between two adjacent purines on the same DNA strand (intrastrand) and to a lesser extent on two opposite strands (interstrand) (Jamieson & Lippard, 1999). Both intra- and interstrand cross-links strongly block replicative DNA polymerases (Comess, Burstyn, Essigmann, & Lippard, 1992), allowing cisplatin to target fast-proliferating cells such as cancer cells to trigger apoptosis. These cross-links also inhibit gene transcription by stalling RNA polymerase (Todd & Lippard, 2009), which is another known mechanism leading to cell death. Hence, the published studies support the mechanism that cisplatin induces cytotoxic DNA damage to exert its anti-tumor activity.

Since the FDA approval, cisplatin and its analogs such as carboplatin and oxaliplatin have been used in the treatment of a wide range of cancers, such as testicular, bladder, head and neck, lung, ovarian, and cervical cancer (Dasari & Tchounwou, 2014). Although many tumors are initially sensitive, they gain resistance during the treatment. Studies from the past 40 years have identified several mechanisms underlying cisplatin resistance, including low drug uptake and high efflux, low yields of cisplatin adduct formation, bypass or repair of cisplatin damage, suppression of cell death signaling, tumor heterogeneity, and others (Galluzzi et al., 2012). In addition to frequent drug resistance, another challenge in cisplatin therapy is side effects that impact kidney, gastrointestinal, and neuronal functions. A total of around 40 specific side effects has been reported and they significantly limit the dose allowed for some patients (Oun, Moussa, & Wheate, 2018).

Combination therapies using platinum and other drugs have been used to overcome the challenges associated with platinum monotherapy (Yu et al., 2020). The combination of different drugs may decrease the therapeutic dose of each individual drug and thus reduce side effects. Combination therapy may also bring synergies with greater treatment efficacy compared to each drug as a single agent. Many different combination therapies have been approved by FDA, including paclitaxel (microtubule inhibitor) and carboplatin, pemetrexed (folic acid analog) and cisplatin, gemcitabine (nucleoside analog) and cisplatin, etc.

New and targeted cancer treatment strategies have emerged in recent years. Among them, PARP inhibitors and immunotherapy have shown significant potency and treatment benefits. Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes that play key roles in DNA repair (Ray Chaudhuri & Nussenzweig, 2017). PARP inhibitors induce synthetic lethality in BRCA1 or BRCA2-deficient tumors and are used for cancer treatment (Mateo et al., 2019). PARP1, the first identified PARP member, is a sensor protein for various types of DNA lesions, including single strand breaks (SSBs) (Eustermann et al., 2011; Satoh & Lindahl, 1992) and double strand breaks (DSBs) (Langelier, Planck, Roy, & Pascal, 2012). Its binding to damaged DNA activates the enzymatic activity, leading to rapid ADP-ribosylation of itself and other substrate proteins. ADP-ribosylation is a post-translational modification recognized by downstream repair factors, thus enhancing recruitment of DNA repair proteins to facilitate DNA repair of strand breaks (Huang & Kraus, 2022). PARP1 also binds to cisplatin-induced cross-link damage (Zhu, Chang, & Lippard, 2010), and participates in replication fork repair and restart (Bryant et al., 2009; Ronson et al., 2018). Therefore, PARP proteins may help cancer cells repair or tolerate cisplatin-induced DNA adducts. Suppression of PARPs represents a therapeutic opportunity to target DNA repair and enhance cancer response to platinum treatment. Indeed, pre-clinical and clinical studies have shown synergistic effects between platinum and PARP inhibitors in cancer cells (Bhattacharjee et al., 2022) and patients (Rodler et al., 2023).

Immune checkpoint inhibitors (ICIs), such as monoclonal antibodies blocking programmed cell death protein 1 (PD-1) and its ligand (PD-L1), are a novel class of immunotherapy drugs that have revolutionized cancer treatment. Several anti-PD-1 and anti-PD-L1 antibodies have been approved by FDA. These blocking antibodies inhibit PD-1 and PD-L1, enabling immune system to recognize tumor-specific mutant antigens (i.e., neoantigens) and unleash anti-tumor immunity (Gubin et al., 2014). Intriguingly, platinum-based chemotherapy has important immunomodulatory effects through multiple mechanisms, including enhancing major histocompatibility complex (MHC) expression in cancer cells, improving recognition of MHC by cytotoxic T-cell (CTL), and downregulating the immunosuppressive microenvironment (de Biasi, Villena-Vargas, & Adusumilli, 2014). Combination of platinum with immunotherapy may provide synergy and extend platinum's traditional role as a DNA damaging agent (Sordo-Bahamonde et al., 2023).

In this Review, we discuss the molecular mechanism for cisplatin cytotoxicity and cellular repair pathways. We further discuss how the combination of platinum with PARP inhibitors and ICIs may overcome many drawbacks associated with platinum monotherapy and deliver better outcomes.