Drug Repurposing of Pantoprazole and Vitamin C Targeting Tumor Microenvironment Conditions Improves Anticancer Effect in Metastatic Castration-Resistant Prostate Cancer.

Zhoulei Li,Christof Seidl,Bing Zhang,Peng He,Gang Yuan,Dianchao Yue,Xiangsong Zhang,Yue Wang,Yali Long,Wanqing Shen,Zhifeng Chen

doi:10.3389/fonc.2021.660320

Abstract

The effective and economical therapeutic strategy for metastatic castration-resistant prostate cancer (mCRPC) is still requested from patients, who are not available for Lu-177 or Ra-223 treatment. Drug repurposing as a cost-effective and time-saving alternative to traditional drug development has been increasingly discussed. Proton pump inhibitors (PPIs) such as pantroprazole, which are commonly used as antacids, have also been shown to be effective in cancer chemoprevention via induction of apoptosis in multiple cancer cell lines. Vitamin C is an essential micronutrient for human body, has been proposed as a potential anti-cancer agent. In this context, have we investigated the combination of vitamin C and pantoprazole for the management of metastatic castration-resistant prostate cancer (mCRPC). Six chosen human adenocarcinoma cell lines were used to investigate the influence of pantoprazole on the microenvironment of cancer cells (extracellular pH and production of exosomes). Tumor growth and tumor 18F-FDG uptake in PC3 xenografts were analyzed following varied treatment. Our in vitro Results have suggested that pantoprazole enhanced the cytotoxic activity of vitamin C by regulating pH values and production of exosomes in cancer cells. Moreover, the synergistic effect of pantoprazole and vitamin C was pH-dependent since pantoprazole was more effective at a slightly acidic pH. In vivo, the combined treatment using pantoprazole and vitamin C produced better therapeutic outcomes than treatment with vitamin C or pantoprazole alone, as demonstrated via tumor growth and uptake of 18F-FDG. Therefore, we suggest that pantoprazole combined with vitamin C could be as a possible strategy to manage mCRPC.

Highlights

Prostate cancer is the second most common cancer in men worldwide and the sixth most common cancer in men in China [1, 2]
As determined by the WST-8 assay, in cell culture medium with an acidic pH (6.5), the proliferation of most cancer cells except OVCAR3 cells was unaffected by the combination of vitamin C and pantoprazole when the compounds were administered simultaneously (Figure 1A and Supplement 1)
When cells were pretreated with pantoprazole for 24 h, pantoprazole single treatment caused a reduction in the viability of PC3 prostate cancer cells to 0.4 units and in DU145 prostate cancer cells to 0.7 units (Figure 1A)

Summary

Introduction

Prostate cancer is the second most common cancer in men worldwide and the sixth most common cancer in men in China [1, 2]. Radiotherapy is an alternative therapeutic choice for patients with CRPC [3], the relapse presented following radiation therapy in 30–50% patients still [4, 5].One new and very effective strategy involves the administration of radio-ligands that target prostate-specific membrane antigen (PSMA), which is overexpressed in prostate cancer cells. For this purpose, both the beta-emitter Lu-177 and the alpha-emitter Ac-225 are coupled to PSMA-617 or PSMAI&T targeting metastatic prostate cancer cells [6, 7].these therapies are not promoted by the China Food and Drug Administration (CFDA). We could demonstrate that sulfasalazine, which is used for the treatment of inflammatory arthritis and inflammatory bowel diseases, improves the anticancer effect of pharmacological vitamin C in mCRPC cells [10]

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Discussion

Conclusion