Cisplatin and other platinum-based drugs, such as carboplatin, ormaplatin, and oxaliplatin, have been widely used to treat a multitude of human cancers. However, a considerable proportion of patients often relapse due to drug resistance and/or toxicity to multiple organs including the liver, kidneys, gastrointestinal tract, and the cardiovascular, hematologic, and nervous systems. In this study, we sought to provide a comprehensive review of the current state of the science highlighting the use of cisplatin in cancer therapy, with a special emphasis on its molecular mechanisms of action, and treatment modalities including the combination therapy with natural products. Hence, we searched the literature using various scientific databases., such as MEDLINE, PubMed, Google Scholar, and relevant sources, to collect and review relevant publications on cisplatin, natural products, combination therapy, uses in cancer treatment, modes of action, and therapeutic strategies. Our search results revealed that new strategic approaches for cancer treatment, including the combination therapy of cisplatin and natural products, have been evaluated with some degree of success. Scientific evidence from both in vitro and in vivo studies demonstrates that many medicinal plants contain bioactive compounds that are promising candidates for the treatment of human diseases, and therefore represent an excellent source for drug discovery. In preclinical studies, it has been demonstrated that natural products not only enhance the therapeutic activity of cisplatin but also attenuate its chemotherapy-induced toxicity. Many experimental studies have also reported that natural products exert their therapeutic action by triggering apoptosis through modulation of mitogen-activated protein kinase (MAPK) and p53 signal transduction pathways and enhancement of cisplatin chemosensitivity. Furthermore, natural products protect against cisplatin-induced organ toxicity by modulating several gene transcription factors and inducing cell death through apoptosis and/or necrosis. In addition, formulations of cisplatin with polymeric, lipid, inorganic, and carbon-based nano-drug delivery systems have been found to delay drug release, prolong half-life, and reduce systemic toxicity while other formulations, such as nanocapsules, nanogels, and hydrogels, have been reported to enhance cell penetration, target cancer cells, and inhibit tumor progression.

Several epidemiological and experimental studies have demonstrated that many human diseases are not only caused by specific genetic and environmental factors but also by gene–environment interactions. Although it has been widely reported that genetic polymorphisms play a critical role in human susceptibility to cancer and other chronic disease conditions, many single nucleotide polymorphisms (SNPs) are caused by somatic mutations resulting from human exposure to environmental stressors. Scientific evidence suggests that the etiology of many chronic illnesses is caused by the joint effect between genetics and the environment. Research has also pointed out that the interactions of environmental factors with specific allelic variants highly modulate the susceptibility to diseases. Hence, many scientific discoveries on gene–environment interactions have elucidated the impact of their combined effect on the incidence and/or prevalence rate of human diseases. In this review, we provide an overview of the nature of gene–environment interactions, and discuss their role in human cancers, with special emphases on lung, colorectal, bladder, breast, ovarian, and prostate cancers.

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