Alpha-lipoic acid alters the antitumor effect of bortezomib in melanoma cells in vitro

Angéla Takács,Orsolya Láng,Eszter Lajkó,Ildikó Istenes,László Kőhidai

doi:10.1038/s41598-020-71138-z

Abstract

Bortezomib (BOZ) is a proteasome inhibitor chemotherapeutic agent utilized to treat multiple myeloma and recently offered to cure melanoma. Bortezomib-induced neuropathy is one of the dose-limiting side-effects, which can be treated with antioxidants (e.g. alpha-lipoic acid—ALA and Vitamin B1—vit B1). We hypothesized that these antioxidants may counteract the antitumor activity by disrupting the BOZ-induced pathways (e.g. proteasome inhibition or reactive oxygen species generation). The objectives were: (i) to verify the anti-proliferative effect of BOZ; (ii) to compare the influence of the antioxidants on the antitumor effect of BOZ in melanoma (A2058) and myeloma (U266) cells. At first, the reduction in the anti-proliferative effect of BOZ by ALA was proved in melanoma cells. Analysis of p53 phosphorylation and the cell cycle progression revealed that ALA failed to counteract these effects of BOZ. Nevertheless, a good correlation was found between the inhibition of the anti-proliferative effect, the anti-proteasome activity and the oxidative stress level after the co-treatment with 20 ng/mL BOZ + 100 μg/mL ALA. Downregulation of apoptotic proteins such as HO-1 and Claspin along with the inhibition of the cleavage of Caspase-3 indicated the proteomic background of the altered responsiveness of the melanoma cells exposed to BOZ + ALA. This phenomenon draws attention to the proper application of cancer supportive care to avoid possible interactions.

Highlights

Bortezomib (BOZ) is a proteasome inhibitor chemotherapeutic agent utilized to treat multiple myeloma and recently offered to cure melanoma
We determined the IC50 values in the 24th hour of the BOZ treatment on both cell lines (A2058—IC50: 158 nM; U266—IC50: 2.17 nM). Based on these IC50 values, the A2058 melanoma cell line showed a 72-fold less sensitivity to BOZ compared with the U266 myeloma cells (Fig. 1A,B)
The concentrations were chosen based on their maximal plasma concentrations (Cmax) that occur after the clinical use[23,24,25], since in case of BOZ, the Cmax was indicated to determine the incidence of bortezomib-induced peripheral neuropathy (BIPN)

Summary

Introduction

Bortezomib (BOZ) is a proteasome inhibitor chemotherapeutic agent utilized to treat multiple myeloma and recently offered to cure melanoma. Bortezomib-induced neuropathy is one of the dose-limiting side-effects, which can be treated with antioxidants (e.g. alpha-lipoic acid—ALA and Vitamin B1—vit B1) We hypothesized that these antioxidants may counteract the antitumor activity by disrupting the BOZ-induced pathways (e.g. proteasome inhibition or reactive oxygen species generation). To optimize the quality of life of the patients, different types of CIPN can be treated with antiepileptic agents, such as gabapentin, antidepressants, such as amitriptyline and neuroprotective or antioxidant vitamins, such as Vitamin C 17,18 These antioxidant vitamins are over-the-counter (OTC) products and are the part of the cancer supportive care that has a growing market nowadays. Cancer supportive care is aimed to focus on the quality of life during the treatments of cancerous illnesses but many times it may decrease the antitumor effect of the chemotherapeutic agent Patients can buy these OTC products in order to help to manage the symptoms of chemotherapy-related side effects without recognizing the potential risks. Several studies have been carried out on the antagonizing effect of Vitamin C on the anticancer effect of antineoplastic m edicines[17,19]

Objectives

Methods

Results

Conclusion