Abstract
Cisplatin is the first-line treatment for different types of solid tumors, such as ovarian, testicular, bladder, cervical, head and neck, lung, and esophageal cancers. The main problem related to its clinical use is the onset of drug resistance. In the last decades, among the studied molecular mechanisms of cisplatin resistance, metabolic reprogramming has emerged as a possible one. This review focuses on the pentose phosphate pathway (PPP) playing a pivotal role in maintaining the high cell proliferation rate and representing an advantage for cancer cells. In particular, the oxidative branch of PPP plays a role in oxidative stress and seems to be involved in cisplatin resistance. In light of these considerations, it has been demonstrated that overexpression and higher enzymatic activity of different enzymes of both oxidative and non-oxidative branches (such as glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and transketolase) increase cisplatin resistance, and their silencing or combined treatment with cisplatin could restore cisplatin sensitivity. Moreover, drug delivery systems loaded with both PPP inhibitors and cisplatin give the possibility of reaching cancer cells selectively. In conclusion, targeting PPP is becoming a strategy to overcome cisplatin resistance; however, further studies are required to better understand the mechanisms.
Highlights
Cis-diamminedichloroplatinum (II), known as cis-platinum or cisplatin (CDDP), synthesized in 1844 by Michele Peyrone, is still considered as first-line treatment for many human solid tumors, such as ovarian, testicular, or head and neck cancers [1,2,3,4,5,6].Despite its use as first-line treatment, one of the main factors that hamper the effectiveness of the therapy is the onset of drug resistance, which leads to tumor relapse and clinical failure [3,6]
This review focuses on the pentose phosphate pathway (PPP) playing a pivotal role in maintaining the high cell proliferation rate and representing an advantage for cancer cells
The formation of adducts with glutathione (GSH), metallothioneins, and other “scavengers” with nucleophilic properties is another well-known mechanism of resistance; in different types of solid tumors, the sequestration by these nucleophilic species has been demonstrated to inactivate the drug leading to increased cellular survival [6]
Summary
Cis-diamminedichloroplatinum (II), known as cis-platinum or cisplatin (CDDP), synthesized in 1844 by Michele Peyrone, is still considered as first-line treatment for many human solid tumors, such as ovarian, testicular, or head and neck cancers [1,2,3,4,5,6]. Several studies demonstrated that the metabolic reprogramming of tumor cells, which is already known as a hallmark of cancer, has been playing an important role in the onset of chemotherapy resistance [12,13]. Cancer cells reprogram their metabolism rewiring their biological pathways in order to maintain a higher proliferation rate, to increase invasion and migration, to avoid apoptosis and growth suppressors, and to induce angiogenesis [14]. We will focus our attention on metabolic reprogramming, on the pentose phosphate pathway (PPP) and its involvement in the onset of cisplatin resistance
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