cisplatin
cisplatin
Overview
Cisplatin (cis-diamminedichloroplatinum(II); CDDP) is a platinum-based chemotherapeutic agent and one of the most widely used cytotoxic drugs in oncology. First approved for clinical use in the late 1970s, it exerts its antitumor activity primarily by forming intra- and interstrand crosslinks with genomic DNA, particularly at guanine residues, thereby inducing DNA damage, stalling replication and transcription, and ultimately triggering apoptosis in rapidly dividing cancer cells. Cisplatin is classified as a cell-cycle non-specific alkylating-like agent, though it is chemically distinct from classical alkylators; its mechanism converges on the DNA damage response network, implicating proteins such as TP53 and downstream effectors of the PI3K/Akt signaling pathway. The drug is active across a broad spectrum of solid tumors and is frequently combined with gemcitabine, doxorubicin, methotrexate, paclitaxel, Nab-Paclitaxel, fluorouracil, and immune checkpoint inhibitors such as pembrolizumab, nivolumab, and durvalumab.
Despite its efficacy, cisplatin use is substantially constrained by two major clinical challenges: severe systemic toxicity—most notably nephrotoxicity, ototoxicity, myelosuppression, and nausea—and the development of intrinsic or acquired resistance in tumor cells. These limitations have driven extensive translational research aimed at identifying resistance mechanisms, mitigating adverse effects, and designing rational combination strategies or novel delivery systems to expand the therapeutic window of cisplatin-based regimens across multiple cancer types.
Recent Publications Focus
Below is a summary of the newest research publications targeting cisplatin (sorted by publication date).
Recent investigations underscore cisplatin's enduring role as a cornerstone chemotherapeutic agent across diverse malignancies—including urothelial, lung, ovarian, gastric, cervical, and head-and-neck cancers—while highlighting the pressing challenge of drug resistance. A key mechanism of resistance involves aberrant reexpression of the synaptonemal complex protein SYCP1 in tumor cells, which promotes DNA repair, cell cycle progression, and chemoresistance; loss of SYCP1 sensitizes cells to cisplatin and gemcitabine [42418586]. Similarly, elevated expression of NAT10, which catalyzes N4-acetylcytidine modifications, enhances cisplatin resistance in gastric cancer by stabilizing DUSP1 mRNA, while NAT10 knockdown restores cisplatin sensitivity [41956987]. Other resistance-associated molecular players include the EXOSC family of RNA processing genes, where EXOSC9 expression correlates with predicted cisplatin sensitivity in lung adenocarcinoma [42171853], and RUNX2 S-palmitoylation, which suppresses ferroptosis and enhances chemoresistance in ovarian cancer via the YAP1/GLS1 axis [42149203].
To overcome cisplatin resistance and enhance efficacy, researchers have pursued multiple combination strategies. Immunotherapy combinations have emerged as a clinical priority: enfortumab vedotin plus pembrolizumab now represents preferred first-line treatment for metastatic urothelial carcinoma [42384383], while durvalumab combined with gemcitabine and cisplatin as neoadjuvant therapy followed by adjuvant durvalumab significantly improved event-free and overall survival in muscle-invasive bladder cancer [41678313]. nivolumab-based chemoradiotherapy sparing concurrent cisplatin was feasible and effective in nasopharyngeal carcinoma [41690301]. Beyond immunotherapy, cisplatin has been synergized with targeted agents and small molecules: simvastatin downregulates caveolin-1-mediated PI3K/AKT signaling to restore cisplatin sensitivity in cervical cancer cells [42087353], a novel Mcl-1 inhibitor (N5) overcomes cisplatin resistance in ovarian cancer [42084733], and advanced Pt(IV) prodrugs targeting thioredoxin reductase simultaneously induce ferroptosis and immunogenic cell death in triple-negative breast cancer [41992775]. Natural products have also shown promise: ginsenoside Rg3 potentiates cisplatin's antitumor activity in lung cancer while protecting against nephrotoxicity through SIRT1-mediated suppression of the NLRP3 inflammasome [42169649], and berberine enhances cisplatin efficacy in Ehrlich ascites carcinoma while ameliorating hepato-renal toxicity [42049890]. Methionine restriction combined with reduced-dose cisplatin demonstrated efficacy against experimental lung-cancer bone metastases [42379791], and cannabinoids (THC and CBD) showed antiproliferative effects when combined with cisplatin in cervical cancer cells [42055476].
Cisplatin-induced toxicity remains a critical barrier to treatment, prompting parallel investigations into protective strategies. Cisplatin-induced acute kidney injury (AKI) can be monitored via body weight changes as a proxy for fluid balance during therapy [42049447] and mitigated by Shiwei Hezi Pill, a Tibetan polyherbal remedy that works through integrative molecular pathways [41747788], or by pretreatment with Oroxylum indicum root bark extract [40991455]. Sodium thiosulfate prophylaxis combined with hyperthermic intraperitoneal chemotherapy (HIPEC) cisplatin in ovarian cancer showed potential in preventing AKI [42047121]. Ototoxicity, a debilitating long-term sequela, results from cisplatin-induced irreversible damage to the stria vascularis and hair cells; current clinical practice is evolving toward baseline audiological screening and high-frequency auditory assessments as standards of care [41987345].
Emerging precision-medicine approaches leverage computational and molecular profiling to predict cisplatin response and refine patient selection. A deep-learning model trained on RNA-sequencing data successfully predicted gemcitabine-and-cisplatin chemotherapy response in urothelial carcinoma patients [42055629]. A robust five-gene signature (ANKRD29/CACNA2D2/DSP/HSD17B6/SPP1) identified via spatial transcriptomics and consensus clustering achieved exceptional diagnostic accuracy (AUC = 0.9639) in stratifying platinum resistance in lung adenocarcinoma; functional validation confirmed that ANKRD29 and CACNA2D2 overexpression sensitized cells to cisplatin, while DSP, SPP1, and HSD17B6 overexpression induced resistance [41662930]. FDG PET/CT-derived parameters emerged as potential prognostic biomarkers in advanced biliary tract cancer patients receiving gemcitabine, cisplatin, and nab-paclitaxel [41627846]. Additionally, advanced nanotheranostic platforms have been engineered to overcome resistance: hierarchical calcium carbonate nanoreactors coloaded with cisplatin and vanadium carbide MXene nanozymes reverse chemoresistance in hepatocellular carcinoma by inducing mitochondrial bioenergetic crisis and inhibiting ATP-dependent DNA repair [41984466], while liposomal encapsulation of a novel ruthenium organometallic compound demonstrated superior cytotoxicity and better tolerability compared to cisplatin in osteosarcoma models [42116576]. Finally, DNA-damage-response-targeted approaches such as the selective ATR inhibitor berzosertib combined with cisplatin and radiation showed clinical feasibility in locally advanced head-and-neck squamous cell carcinoma [41823504], and PARP1-targeted Pt(II) conjugates achieved higher tumor-growth inhibition than cisplatin alone while exhibiting lower systemic toxicity in ovarian cancer xenografts [41996568].