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.

Keywords: cancer; cisplatin; drug delivery systems; pentose phosphate pathway; resistance.

Figure 1

The pentose phosphate pathway (PPP) is a metabolic pathway involved in the onset of cisplatin resistance. The oxidative branch (red frames) comprises three reactions: the first one involves the enzyme glucose 6-phosphate dehydrogenase (G6PD); the second reaction is catalyzed by phosphogluconolactonase (6PGL); the third reaction involves the enzyme 6-phosphogluconate dehydrogenase (6PGD). The non-oxidative branch (green frames) comprises other reactions and the enzymes involved are transketolase (TKT) and transaldolase (TAL).

Figure 2

Graphical view of the metabolic and molecular effects of the combined treatment with PPP inhibitors and cisplatin (CDDP). The symbol ――| indicates inhibition of the enzymes G6PD and 6PGD. The inhibition of the enzyme leads to increased ROS accumulation and resensitization of CDDP-resistant cells. G6PD: glucose 6-phosphate dehydrogenase; 6PGL: phosphogluconolactonase; 6PGD: 6-phosphogluconate dehydrogenase.