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.

Focus of Latest Publications

Recent publications demonstrate cisplatin's continued role as a cornerstone chemotherapy across multiple cancer types, including urothelial carcinoma, lung cancer, ovarian cancer, cervical cancer, and head and neck squamous cell carcinoma, with emerging focus on combination strategies to enhance efficacy and overcome intrinsic barriers. Cisplatin-based regimens remain standard-of-care neoadjuvant treatment for muscle-invasive bladder cancer, with recent phase III evidence supporting durvalumab added to gemcitabine and cisplatin followed by adjuvant durvalumab, demonstrating improved event-free survival and overall survival compared to chemotherapy alone. In nasopharyngeal carcinoma and head and neck cancers, immunotherapy-based regimens are being explored as alternatives that spare concurrent cisplatin exposure while maintaining efficacy, with patient-reported outcomes supporting improved quality of life with these approaches.

A substantial body of recent work has focused on reversing cisplatin resistance through targeted molecular interventions. Multiple studies identified genetic and protein signatures predictive of platinum sensitivity in lung adenocarcinoma, including a 5-gene model (ANKRD29/CACNA2D2/DSP/HSD17B6/SPP1) that achieved diagnostic-level accuracy. At the mechanistic level, investigators demonstrated that cisplatin resistance involves multifaceted pathways: RUNX2 palmitoylation via ZDHHC14 attenuates ferroptosis and confers ovarian cancer chemoresistance, while NAT10-mediated ac4C mRNA modification of DUSP1 promotes gastric cancer cisplatin resistance through JNK/ERK signaling. Novel agents targeting these resistance mechanisms showed promise, including a tetrahydro-β-carboline MCL-1 inhibitor and parp1-targeted platinum conjugates that demonstrated superior efficacy over cisplatin alone in ovarian cancer xenografts.

Alternative chemotherapy formulations and adjuvant compounds emerged as strategies to overcome cisplatin limitations. Liposomal encapsulation of a ruthenium organometallic compound (Ru3) outperformed free cisplatin in cisplatin-resistant osteosarcoma models, with improved tolerability and selective activity against cancer stem cell-enriched tumorspheres. Emerging nanotheranostic approaches, including biowaste-derived calcium carbonate nanoreactors coloading cisplatin and vanadium carbide MXene, induced mitochondrial bioenergetic crisis and reversed cisplatin resistance in hepatocellular carcinoma by deactivating ATP-dependent DNA repair machinery. Platinum(IV) prodrugs targeting thioredoxin reductase demonstrated dual capacity to induce ferroptosis and immunogenic cell death in triple-negative breast cancer, suggesting synergy between metabolic cell death pathways and immune activation as a strategy to enhance cisplatin sensitivity.

Complementary pharmacological interventions showed potential to enhance cisplatin efficacy while mitigating toxicity. Ginsenoside Rg3 combined with cisplatin augmented apoptosis in lung carcinoma cells and improved survival in xenograft models while suppressing cisplatin-induced nephrotoxicity through SIRT1-mediated NLRP3 inflammasome inhibition. Simvastatin restored cisplatin sensitivity in resistant cervical cancer cells by downregulating caveolin-1 and the PI3K/AKT pathway, with in vivo synergy confirmed. berberine, a plant alkaloid, enhanced cisplatin antitumor efficacy in an ascites carcinoma model and ameliorated hepatorenal toxicity through modulation of PI3K/Akt signaling and efferocytosis.

Clinical management of cisplatin toxicity received sustained attention, with studies defining monitoring strategies for cisplatin-induced acute kidney injury, including body weight-based fluid balance assessment and sodium thiosulfate administration during hyperthermic intraperitoneal chemotherapy. Systematic review of cisplatin-induced ototoxicity highlighted molecular mechanisms of inner-ear damage and advocated for baseline audiological screening and high-frequency assessments as standards of care. Traditional medicine approaches, including Shiwei Hezi Pill and Oroxylum indicum root bark extract, showed hepatorenal protective effects in preclinical models, suggesting complementary strategies to preserve organ function during platinum-based chemotherapy.

Key Publications

• NEWJul First-Line Enfortumab Vedotin Plus Pembrolizumab vs Gemcitabine Plus Cisplatin for Metastatic Urothelial Carcinoma. (JAMA network open, 2026, PMID 42384383): "Enfortumab vedotin plus pembrolizumab (EV/P) recently emerged as the preferred first-line treatment regimen for metastatic urothelial carcinoma (mUC), but evidence outside trial settings is relatively limited."
• NEWJan Synergy of a Low-methionine Diet and Reduced-dose Cisplatinum Eradicates Experimental Lung-cancer Bone Metastases in a Nude-mouse Model. (In vivo (Athens, Greece), 2026, PMID 42379791): "The present study aimed to evaluate the efficacy of MR combined with low-dose cisplatinum on an experimental nude-mouse model of bone metastasis of lung cancer."
• Jul Ginsenoside Rg3 potentiates cisplatin antitumor activity while mitigating nephrotoxicity through SIRT1‑mediated suppression of the NLRP3 inflammasome. (International journal of molecular medicine, 2026, PMID 42169649): "However, its use is limited by nephrotoxicity and drug resistance."
• May Comprehensive bioinformatics analysis of EXOSC family genes in lung adenocarcinoma. (Discover oncology, 2026, PMID 42171853): "Exploratory translational analyses further indicated an association between EXOSC9 and predicted cisplatin sensitivity."
• May ZDHHC14-driven RUNX2 S-palmitoylation attenuates ferroptosis and enhances chemoresistance in ovarian cancer via the YAP1/GLS1 axis. (Apoptosis : an international journal on programmed cell death, 2026, PMID 42149203): "This study aimed to investigate the role of RUNX2 in regulating ferroptosis and cisplatin (CDDP) resistance in OC, along with its post-translational modification mechanisms."
• May Chemotherapy-induced anemia as a prognostic factor for overall survival in patients with bladder cancer treated with neoadjuvant cisplatin-based chemotherapy and cystectomy. (World journal of urology, 2026, PMID 42132947): "Chemotherapy-induced anemia as a prognostic factor for overall survival in patients with bladder cancer treated with neoadjuvant cisplatin-based chemotherapy and cystectomy."
• May Liposome-mediated delivery of a ruthenium-based metallodrug to overcome cisplatin resistance in osteosarcoma. (Drug delivery, 2026, PMID 42116576): "However, like other cytotoxic drugs, cisplatin is limited by severe systemic toxicity and the development of resistance."
• May [Expression of Concern] ISL1 promotes cancer progression and inhibits cisplatin sensitivity in triple‑negative breast cancer cells. (International journal of molecular medicine, 2026, PMID 42099237): "ISL1 promotes cancer progression and inhibits cisplatin sensitivity in triple-negative breast cancer cells."
• May Simvastatin Restores Cisplatin Sensitivity by Suppressing the Caveolin-1-Mediated PI3K/AKT Signaling Pathway in Cisplatin-Resistant Cervical Cancer Cells. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 42087353): "Cervical cancer treatment is often hindered by the emergence of cisplatin (DDP) resistance."
• May Discovery of a Novel Tetrahydro-β-Carboline Mcl-1 Inhibitor with Antitumor Activity and Capability to Overcome Cisplatin Resistance. (Journal of medicinal chemistry, 2026, PMID 42084733): "Notably, its hydrochloride (designated N5Y) exhibited even better antitumor efficacy as a single agent and the ability to overcome cisplatin resistance, producing significant synergistic effects in combination therapy."