Abstract: Cisplatin is a highly effective, first-generation platinum-based chemotherapeutic agent widely utilized in the treatment of various solid tumors, including ovarian, breast, lung, and colorectal cancers. Despite its potent ability to induce DNA damage and subsequent apoptosis in rapidly proliferating cancer cells, the clinical utility of cisplatin is significantly hindered by severe dose-limiting side effects, most notably nephrotoxicity, as well as the frequent development of intrinsic or acquired drug resistance. To overcome these challenges, current research heavily focuses on combination therapy strategies. This comprehensive literature review explores the pharmacological activity, molecular mechanisms, and structure-activity relationships of cisplatin. Furthermore, it highlights current limitations and future perspectives, emphasizing the integration of cisplatin with targeted inhibitors, immunotherapies, radiotherapy, and advanced nanoparticle delivery systems to enhance anti-tumor efficacy while mitigating systemic toxicity.
1. Introduction
Cisplatin (cis-diamminedichloroplatinum(II)) is a pioneering first-generation platinum-based anti-cancer drug that was discovered in the late 1960s and officially approved for clinical cancer treatment in 1978 [4]. It has since become a cornerstone in the chemotherapeutic eradication of numerous malignant solid tumors, including breast, ovarian, colorectal, and lung cancers [4]. The primary mechanism of cisplatin involves binding to DNA to form crosslinks, which disrupts DNA replication and transcription, ultimately leading to cell cycle arrest and apoptosis [4].
However, as a non-specific chemotherapeutic agent, cisplatin causes severe systemic toxicities, including nephrotoxicity, neurotoxicity, ototoxicity, and myelosuppression, which severely limit its long-term clinical application [1] [4]. Furthermore, tumor cells frequently develop resistance to cisplatin through mechanisms such as decreased drug influx, enhanced drug efflux, intracellular detoxification by glutathione (GSH), and increased DNA repair capacity [2] [4]. To address these critical limitations, modern oncological research has pivoted towards combination therapies. By combining cisplatin with other chemotherapeutic agents, targeted molecular inhibitors, radiotherapy, immunotherapy, and utilizing advanced nanocarrier delivery systems, researchers aim to synergistically enhance anti-tumor efficacy while minimizing adverse systemic effects [2] [3] [4].
2. Pharmacological Activity
Cisplatin exhibits potent cytostatic and cytotoxic properties against rapidly dividing cells. In clinical practice, it is rarely used as a standalone treatment; instead, it serves as a foundational component in various combination regimens. For instance, in the treatment of advanced ovarian cancer, the combination of cisplatin and paclitaxel has long been a standard first-line therapy [2]. In stage I-III squamous cell anal cancer, chemoradiation therapy (CRT) combining 5-fluorouracil (5-FU) with cisplatin or mitomycin C has been shown to provide significant benefits in locoregional failure, disease-specific survival, and colostomy-free survival [7].
Cisplatin also acts as a potent radiosensitizer. When combined with radiotherapy, cisplatin concentrates radiation in the vicinity of targeted cellular DNA, significantly enhancing the formation of DNA single- and double-strand breaks [3]. Furthermore, recent clinical trials are actively exploring the combination of cisplatin-based chemotherapy with immune checkpoint inhibitors (e.g., PD-1/PD-L1 inhibitors like nivolumab, pembrolizumab, and tislelizumab) to mobilize the immune system, reverse immunosuppression in the tumor microenvironment, and overcome platinum resistance [2] [9].
3. Molecular Mechanism of Action
The molecular mechanism of cisplatin begins with its cellular uptake, which occurs via passive diffusion and facilitated transport mediated by membrane proteins such as copper transporter 1 (CTR1) and organic cation transporters (OCTs) [1] [4]. Once inside the cytoplasm, the significantly lower intracellular chloride ion concentration (approximately 4 mM compared to 100 mM extracellularly) triggers the aquation of cisplatin. The chloro-ligands are replaced by water molecules, converting the drug into highly reactive cationic hydrates, such as cis-[Pt(NH3)2Cl(OH2)]+ and cis-[Pt(NH3)2(OH2)2]2+ [4].
These activated platinum complexes enter the nucleus and preferentially bind to the N7 position of guanine bases in DNA. This binding forms intra-strand and inter-strand crosslinks, which distort the DNA helical structure [4] [8]. The resulting DNA adducts are recognized by damage recognition proteins, which transduce signals downstream to activate cell cycle checkpoints (e.g., via ATR, p53, and MAPK pathways). If the DNA damage is beyond repair, the cell undergoes apoptosis [8]. Beyond DNA damage, cisplatin also exerts cytotoxicity by inducing mitochondrial oxidative stress, endoplasmic reticulum (ER) stress, and acidification of the cytoplasm [4].
4. Structure-Activity Relationship (SAR)
The chemical structure of cisplatin consists of a central platinum(II) ion coordinated to two amine (NH3) ligands and two chloride (Cl-) leaving groups in a strict cis planar geometry [4]. This specific geometric arrangement is critical for its pharmacological activity. Its isomer, transplatin, exhibits a much faster hydration rate and reacts rapidly with intracellular glutathione (GSH). Consequently, transplatin is deactivated before it can reach the nucleus to form stable DNA crosslinks, rendering it clinically ineffective [4].
Modifications to the leaving groups have led to the development of second- and third-generation platinum drugs. Replacing the chloride ligands with bidentate cyclobutane dicarboxylic acid (as in carboplatin) or oxalate (as in oxaliplatin) increases the stability of the complex against aquation. This reduces systemic toxicity—particularly nephrotoxicity and neurotoxicity—and alters the resistance profile, though it can sometimes result in lower overall cytotoxicity compared to cisplatin [1] [4].
Recent SAR advancements involve the oxidation of Pt(II) to Pt(IV) to create photoactive or reduction-sensitive prodrugs. Pt(IV) complexes possess an octahedral geometry, allowing for the attachment of two additional axial ligands. These axial positions can be functionalized with targeting moieties (e.g., folic acid, biotin, or peptides) to enhance tumor-specific delivery. Upon entering the reductive tumor microenvironment, the Pt(IV) prodrug is reduced back to the active Pt(II) species, releasing the drug directly inside the cancer cells [4].
5. Current Limitations
The clinical application of cisplatin is heavily restricted by two major limitations: severe systemic toxicity and the emergence of drug resistance.
Systemic Toxicity: Cisplatin is a non-specific agent that damages normal tissues, particularly the kidneys. Cisplatin-induced nephrotoxicity is a dose-limiting side effect characterized by mitochondrial vacuolation, oxidative stress, lipid peroxidation, and apoptosis in the proximal tubules [1]. This leads to reduced glomerular filtration rates, electrolyte imbalances, and acute kidney injury [1]. Consequently, strict dose adjustments or alternative treatments are required for patients with pre-existing kidney dysfunction, complicating clinical management [5].
Drug Resistance: Tumors frequently develop resistance to cisplatin, leading to relapse. Resistance mechanisms occur at multiple stages: decreased cellular uptake, increased drug efflux via membrane pumps, and cytoplasmic detoxification by high levels of GSH and metallothioneins, which bind and inactivate cisplatin [2] [4]. Furthermore, cancer cells often upregulate DNA repair pathways, such as nucleotide excision repair (NER) and homologous recombination repair (HRR), allowing them to survive otherwise lethal DNA damage [2].
6. Future Perspectives
To overcome the limitations of cisplatin, future therapeutic strategies are heavily focused on advanced combination therapies and targeted delivery systems.
Nanoparticle Delivery Systems: Encapsulating cisplatin in nanocarriers—such as liposomes, polymeric nanoparticles (e.g., PLGA-PEG), and metallic nanoparticles (e.g., gold, silver, and selenium)—offers a promising approach to reduce systemic toxicity and bypass resistance [1] [2] [4]. Nanoparticles can passively accumulate in tumors via the enhanced permeability and retention (EPR) effect and can be engineered to prevent renal clearance, thereby mitigating nephrotoxicity [1]. For example, co-delivery of cisplatin with antioxidants (like curcumin or boldine) in nanoparticles has been shown to protect renal tissues from oxidative stress while maintaining anti-tumor efficacy [1].
Targeted Combination Therapies: Co-administering cisplatin with agents that disrupt resistance mechanisms is a major area of exploration. For instance, combining cisplatin with GSH-scavenging agents (e.g., sulforaphane or DIMATE) depletes intracellular GSH, restoring the sensitivity of resistant cells to platinum [4] [6]. Additionally, combining cisplatin with DNA repair inhibitors, such as PARP inhibitors (e.g., olaparib) or ATR/CHK1 pathway inhibitors, induces synthetic lethality and prevents cancer cells from repairing cisplatin-induced DNA crosslinks [2] [11].
Integration with Immunotherapy and Radiotherapy: The future of cisplatin therapy also lies in its integration with immune checkpoint blockade and precision radiotherapy. Nanoparticles co-delivering cisplatin and radiosensitizers (e.g., catalase to relieve tumor hypoxia) can dramatically enhance chemoradiotherapy outcomes [3]. Concurrently, combining cisplatin with PD-1/PD-L1 inhibitors aims to synergize direct cytotoxicity with robust anti-tumor immune responses, offering hope for durable remissions in refractory cancers [2] [9].
