Abstract: Cisplatin is a highly effective, first-generation platinum-based chemotherapeutic agent widely used in the treatment of various solid tumors, including ovarian, breast, and lung cancers. Despite its potent anti-tumor efficacy, the clinical utility of cisplatin is significantly hindered by severe systemic toxicities, such as nephrotoxicity, and the frequent development of drug resistance. Cisplatin resistance is a multifactorial phenomenon that occurs at several cellular stages: reduced cellular uptake, increased drug efflux, cytoplasmic inactivation by thiols like glutathione (GSH), enhanced DNA damage repair, and evasion of apoptosis. Recent research has focused on elucidating the molecular and epigenetic mechanisms underlying this resistance, including the roles of non-coding RNAs and metabolic reprogramming. To overcome these limitations, novel therapeutic strategies are being developed, including the design of targeted nanoparticle delivery systems, GSH-scavenging platinum prodrugs, and combination therapies with immune checkpoint inhibitors or targeted biological agents. This review comprehensively summarizes the pharmacological activity, molecular mechanisms of resistance, structure-activity relationships, current clinical limitations, and future perspectives of cisplatin in cancer therapy.
1. Introduction
Cisplatin is a pioneering, first-generation platinum-based anti-cancer drug that was discovered in the late 1960s and approved for clinical use in 1978 [2]. It exhibits broad-spectrum and highly efficient anti-tumor activities, making it a cornerstone in the treatment of numerous solid malignancies, including ovarian, breast, colorectal, bladder, and lung cancers [1][2]. For instance, combination chemotherapy based on cisplatin and paclitaxel has long been the standard first-line treatment for advanced ovarian cancer [1]. However, the clinical success of cisplatin is heavily compromised by its non-specific cytotoxicity, which leads to severe dose-limiting side effects such as nephrotoxicity, neurotoxicity, ototoxicity, and myelosuppression [2]. Furthermore, the emergence of intrinsic or acquired drug resistance frequently leads to disease relapse and treatment failure [1]. Consequently, understanding the mechanisms of cisplatin resistance and developing strategies to mitigate its toxicity while enhancing its efficacy remain critical imperatives in oncological research.
2. Pharmacological Activity
The primary pharmacological activity of cisplatin involves its interaction with cellular DNA to induce apoptosis. Upon administration, cisplatin is transported into tumor cells partially through membrane transporters such as copper transporter 1 (CTR1) [2]. Once inside the cell, the drug encounters a significantly lower chloride ion concentration (approximately 4 mM) compared to the extracellular matrix (approximately 100 mM). This concentration gradient triggers the aquation of cisplatin, where its chloro-ligands are replaced by water molecules to form highly reactive cationic hydrates, such as cis-[Pt(NH3)2Cl(OH2)]+ and cis-[Pt(NH3)2(OH2)2]2+ [2]. These reactive platinum species bind to nuclear DNA, forming DNA adducts that cause structural damage. The cisplatin-induced DNA adducts are recognized by damage recognition proteins, which transduce signals to activate cell cycle checkpoints and arrest the cell cycle [5]. If the DNA damage is beyond repair, the cell undergoes apoptosis. Additionally, cisplatin interacts with mitochondria, inducing the production of mitochondrial reactive oxygen species (mtROS), which further dictates the apoptotic fate of the cancer cells [1].
3. Molecular Mechanism of Action
Cisplatin resistance is a complex, multi-stage process that can be categorized into several distinct phases [1]:
- Pre-entry and Transport Alterations: Before entering the cell, cisplatin can be bound and inactivated by plasma proteins like human serum albumin, or hindered by extracellular matrix remodeling (e.g., overexpression of collagen VI and matrix metalloproteinases) [1]. At the membrane level, resistance is mediated by the downregulation of influx transporters (such as CTR1 and organic cation transporters) and the upregulation of efflux pumps (such as ATP7A, ATP7B, and multidrug resistance protein 1/P-glycoprotein), which collectively reduce intracellular drug accumulation [1][3].
- Cytoplasmic Inactivation: In the cytoplasm, cisplatin is highly susceptible to detoxification by sulfur-containing molecules. Glutathione (GSH) and metallothioneins competitively bind to the platinum core, forming inactive adducts that are subsequently pumped out of the cell, preventing the drug from reaching its nuclear DNA target [1][2].
- Enhanced DNA Repair: Cancer cells can develop resistance by upregulating DNA damage repair (DDR) pathways, including nucleotide excision repair (NER), homologous recombination repair (HRR), and mismatch repair (MMR). Overexpression of repair proteins such as ERCC1, XPA, and RAD51 facilitates the rapid removal of cisplatin-DNA adducts, promoting cell survival [1].
- Evasion of Apoptosis and Epigenetic Regulation: Resistant cells often exhibit dysregulated apoptotic pathways, such as p53 mutations or overexpression of anti-apoptotic proteins (e.g., BCL-2, BIRC3) [3]. Furthermore, non-coding RNAs (ncRNAs), including microRNAs (e.g., miR-141, miR-214-3p), long non-coding RNAs (lncRNAs), and circular RNAs, form complex competing endogenous RNA (ceRNA) networks that modulate chemosensitivity by regulating genes involved in apoptosis, epithelial-mesenchymal transition (EMT), and cellular metabolism [1][3][6][7].
4. Structure-Activity Relationship (SAR)
The chemical structure of platinum-based drugs is fundamentally linked to their anti-tumor efficacy and toxicity profiles. Cisplatin is a square planar Pt(II) complex featuring two amine ligands and two chloride leaving groups in a cis configuration. The cis geometry is absolutely critical for its pharmacological activity. In contrast, its isomer transplatin reacts much more rapidly with intracellular nucleophiles; for example, transplatin reacts with 70% of available GSH within 4 hours, compared to only 35% for cisplatin. This high reactivity causes transplatin to be rapidly deactivated before it can reach the nuclear DNA, rendering it therapeutically ineffective [2].
To mitigate the severe toxicities of cisplatin, second- and third-generation platinum drugs were developed by modifying the leaving groups. Carboplatin utilizes a bidentate cyclobutane dicarboxylic acid ligand, while oxaliplatin employs an oxalate ligand. These bidentate ligands significantly lower the hydration rate of the Pt(II) complex, resulting in greater stability, reduced systemic toxicity (such as nephrotoxicity and neurotoxicity), and altered cross-resistance profiles [2][4]. Additionally, Pt(IV) prodrugs are being explored. These complexes maintain a stable +4 valence state in the bloodstream and are selectively reduced to the active +2 valence state within the reductive tumor microenvironment, thereby minimizing off-target effects [2].
5. Current Limitations
The clinical application of cisplatin is primarily limited by two major factors: severe systemic toxicity and the development of drug resistance. Because cisplatin is a non-specific agent, it causes collateral damage to normal tissues. Nephrotoxicity is particularly prominent, as cisplatin accumulates in the proximal tubules of the kidney via organic cation transporter 2 (OCT2), leading to oxidative stress, mitochondrial injury, and renal cell apoptosis [4]. Other dose-limiting toxicities include neurotoxicity, ototoxicity, and myelosuppression [2].
Furthermore, the dynamic evolution of tumor heterogeneity and the presence of cancer stem cells contribute to acquired resistance during long-term therapy [1]. Metabolic reprogramming, such as enhanced glycolysis (the Warburg effect) and altered glutamine metabolism, provides resistant cells with the energy and metabolic intermediates necessary to survive cisplatin-induced stress [1]. While alternative platinum drugs like carboplatin offer reduced toxicity, they often exhibit partial cross-resistance with cisplatin, limiting their efficacy in relapsed patients [1].
6. Future Perspectives
To overcome the limitations of cisplatin, researchers are heavily investing in targeted drug delivery systems and combination therapies. Nanotechnology offers promising solutions through the use of liposomes, polymeric nanoparticles, mesoporous silica, and metallic nanoparticles (e.g., gold and iron oxide). These nanocarriers can improve drug bioavailability, facilitate targeted delivery via the enhanced permeability and retention (EPR) effect or active targeting ligands (e.g., hyaluronic acid, LHRH), and significantly reduce renal accumulation and nephrotoxicity [2][4]. Innovative designs, such as GSH-scavenging Pt(IV) polymeric nanoparticles, can simultaneously deplete intracellular GSH and release active Pt(II), effectively reversing thiol-mediated drug resistance [2][4].
In the clinical realm, combination therapies are being extensively evaluated. Combining cisplatin with PARP inhibitors, cell-cycle kinase inhibitors (e.g., CDK4/6 inhibitors like palbociclib), anti-angiogenic agents, or immune checkpoint inhibitors (e.g., PD-1/PD-L1 antibodies) has shown synergistic effects in overcoming resistance [1]. Additionally, targeting epitranscriptomic and epiproteomic modifications—such as specific miRNAs, lncRNAs, or post-translational modification pathways—presents a novel frontier for resensitizing refractory tumors to cisplatin therapy [3].
