Targeting Lactate Dehydrogenase A with Catechin Resensitizes SNU620/5FU Gastric Cancer Cells to 5-Fluorouracil.

Jung Ho Han,Dongryeol Ryu,Ki-Tae Ha,Se Bok Jang,Hyeon Jin Kim,Minjeong Kim,In-Kyu Lee,Sung-Jin Bae

doi:10.3390/ijms22105406

Abstract

Resistance to anticancer therapeutics occurs in virtually every type of cancer and becomes a major difficulty in cancer treatment. Although 5-fluorouracil (5FU) is the first-line choice of anticancer therapy for gastric cancer, its effectiveness is limited owing to drug resistance. Recently, altered cancer metabolism, including the Warburg effect, a preference for glycolysis rather than oxidative phosphorylation for energy production, has been accepted as a pivotal mechanism regulating resistance to chemotherapy. Thus, we investigated the detailed mechanism and possible usefulness of antiglycolytic agents in ameliorating 5FU resistance using established gastric cancer cell lines, SNU620 and SNU620/5FU. SNU620/5FU, a gastric cancer cell harboring resistance to 5FU, showed much higher lactate production and expression of glycolysis-related enzymes, such as lactate dehydrogenase A (LDHA), than those of the parent SNU620 cells. To limit glycolysis, we examined catechin and its derivatives, which are known anti-inflammatory and anticancer natural products because epigallocatechin gallate has been previously reported as a suppressor of LDHA expression. Catechin, the simplest compound among them, had the highest inhibitory effect on lactate production and LDHA activity. In addition, the combination of 5FU and catechin showed additional cytotoxicity and induced reactive oxygen species (ROS)-mediated apoptosis in SNU620/5FU cells. Thus, based on these results, we suggest catechin as a candidate for the development of a novel adjuvant drug that reduces chemoresistance to 5FU by restricting LDHA.

Highlights

IntroductionRemarkable progress has been achieved in the treatment of gastric cancer with surgical resection of the primary tumor and 5-fluorouracil (5FU)-based combinational chemotherapy, such as epirubicin, cisplatin, and fluorouracil and docetaxel, oxaliplatin, and 5FU [1,2]
Remarkable progress has been achieved in the treatment of gastric cancer with surgical resection of the primary tumor and 5-fluorouracil (5FU)-based combinational chemotherapy, such as epirubicin, cisplatin, and fluorouracil and docetaxel, oxaliplatin, and 5FU [1,2].To date, 5FU, an analog of uracil that blocks DNA synthesis by inhibiting thymidylate synthase [3], remains a commonly used chemotherapy drug for the treatment of gastric cancer [1,4]
Enhanced proliferation is a characteristic of chemoresistance including 5FU-resistant cancer cells [26,27]

Summary

Introduction

Remarkable progress has been achieved in the treatment of gastric cancer with surgical resection of the primary tumor and 5-fluorouracil (5FU)-based combinational chemotherapy, such as epirubicin, cisplatin, and fluorouracil and docetaxel, oxaliplatin, and 5FU [1,2]. Metabolic reprogramming, especially abnormal aerobic glycolysis, has been reported as a key player in the development of resistance to chemotherapeutic drugs, including 5FU, in gastric cancer [9]. LDHA, a key enzyme catalyzing the conversion of pyruvate to lactate, has been reported as a potential target for the treatment of gastric cancer [13,14].

Methods

Results

Conclusion