The Pentose Phosphate Pathway and Its Involvement in Cisplatin Resistance

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.

Artesunate Impairs Growth in Cisplatin-Resistant Bladder Cancer Cells by Cell Cycle Arrest, Apoptosis and Autophagy Induction

“…Adduct formation with glutathione (GSH), methionine, metallothioneins, and other cytoplasmic nucleophiles inactivate cisplatin, maintaining a lower drug concentration within the nucleus [ 4 , 6 ]. Furthermore, metabolic reprogramming is pivotal in cisplatin resistance [ 7 ]. Thus, these mechanisms re-activate cell cycling, tumor growth, and cell survival, and prevent induction of apoptosis, promoting cisplatin resistance [ 4 , 7 ].…”

“…Furthermore, metabolic reprogramming is pivotal in cisplatin resistance [ 7 ]. Thus, these mechanisms re-activate cell cycling, tumor growth, and cell survival, and prevent induction of apoptosis, promoting cisplatin resistance [ 4 , 7 ]. Cisplatin-ineligible, but PD-L1-positive patients with advanced/metastatic bladder cancer can be treated with a carboplatin-based chemotherapy or an immune checkpoint inhibitor.…”

Identification of Metabolic Reprogramming Related Gene Signature to Predict the Prognosis of Bladder Cancer Patients

“…With the hostile environment where solid tumor cells living in like starvation, hypoxia and so on, tumor cells may exchange its patterns of metabolism to adjust the microenvironment ,which is also called metabolic reprogramming [19,20] . It has widely believed that metabolic reprogramming is one of the hallmarks of cancer cells [19,20] , while there were so many ndings aimed to seek out how could it happens and effect on the tumor malignent behaviors [22,23] , our group tried to draw our attention on the prognostic role of metabolic reprogramming. As the report our group members had published before, they had successfully built a four glycolysis related gene signature as a prognostic model based on 19 pairs bladder cancer samples and their adjacent normal samples of BLCA patients [24] .…”

MRP1-Collateral Sensitizers as a Novel Therapeutic Approach in Resistant Cancer Therapy: An In Vitro and In Vivo Study in Lung Resistant Tumor

“…This phenotype is peculiar for drug-resistant MRP1-expressing cells [47], as A549/DX are. The high levels of GSH may protect cells from the oxidative damage induced by cis-Pt [48] and activate the glutathione S-transferase (GST) enzymes that conjugate GSH to cis-Pt and promote its efflux via MRP1 [49].…”