Mefloquine exerts anticancer activity in prostate cancer cells via ROS-mediated modulation of Akt, ERK, JNK and AMPK signaling

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Abstract

Mefloquine (MQ) is a prophylactic anti-malarial drug. Previous studies have shown that MQ induces oxidative stress in vitro. Evidence indicates that reactive oxygen species (ROS) may be used as a therapeutic modality to kill cancer cells. This study investigated whether MQ also inhibits prostate cancer (PCa) cell growth. We used sulforhodamine B (SRB) staining to determine cell viability. MQ has a highly selective cytotoxicity that inhibits PCa cell growth. The antitumor effect was most significant when examined using a colony formation assay. MQ also induces hyperpolarization of the mitochondrial membrane potential (MMP), as well as ROS generation. The blockade of MQ-induced anticancer effects by N-acetyl cysteine (NAC) pre-treatment confirmed the role of ROS. This indicates that the MQ-induced anticancer effects are caused primarily by increased ROS generation. Moreover, we observed that MQ-mediated ROS simultaneously downregulated Akt phosphorylation and activated extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and adenosine monophosphate-activated protein kinase (AMPK) signaling in PC3 cells. These findings provide insights for further anticancer therapeutic options.

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Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial.

Julio Sotelo, Gabriela E. Briceño, Miguel Angel Gonzalez-Torres (2006)

Malignant cell clones resistant to chemotherapy and radiotherapy frequently lead to treatment failure in patients with glioblastoma multiforme. Preliminary studies suggest that adding chloroquine to conventional therapy may improve treatment outcomes. To examine the effect of adding chloroquine to conventional therapy for glioblastoma multiforme. Randomized, double-blind, placebo-controlled trial. National Institute of Neurology and Neurosurgery of Mexico. 30 patients with surgically confirmed glioblastoma confined to 1 cerebral hemisphere, with a Karnofsky performance score greater than 70, no comorbid disease, and age younger than 60 years. Oral chloroquine at 150 mg/d for 12 months beginning on postoperative day 5 or placebo. All patients received conventional chemotherapy and radiotherapy. Primary outcome was survival after surgery; surviving patients were followed up to October 2005. Periodic evaluation using the Karnofsky scale and imaging studies, as well as hematologic tests and ophthalmologic examinations, was done in all patients. Median survival after surgery was 24 months for chloroquine-treated patients and 11 months for controls. At the end of the observation period, 6 patients treated with chloroquine had survived 59, 45, 30, 27, 27, and 20 months, respectively; 3 patients from the control group had survived 32, 25, and 22 months, respectively. Although not statistically significantly different, the rate of death with time was approximately half as large in patients receiving chloroquine as in patients receiving placebo (hazard ratio, 0.52 [95% CI, 0.21 to 1.26]; P = 0.139). The observed advantage of chloroquine may be due to chance; differences in pretreatment characteristics and conventional treatment regimens could not be adjusted for because of the small sample size. Chloroquine may improve mid-term survival when given in addition to conventional therapy for glioblastoma multiforme. These results suggest that larger, more definitive studies of chloroquine as adjuvant therapy for glioblastoma are warranted.

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Mitochondrial ROS generation for regulation of autophagic pathways in cancer.

Zi-yue Li, Yu. Yang, Miao Ming … (2011)

Mitochondria, the main source of reactive oxygen species (ROS), are required for cell survival; yet also orchestrate programmed cell death (PCD), referring to apoptosis and autophagy. Autophagy is an evolutionarily conserved lysosomal degradation process implicated in a wide range of pathological processes, most notably cancer. Accumulating evidence has recently revealed that mitochondria may generate massive ROS that play the essential role for autophagy regulation, and thus sealing the fate of cancer cell. In this review, we summarize mitochondrial function and ROS generation, and also highlight ROS-modulated core autophagic pathways involved in ATG4-ATG8/LC3, Beclin-1, p53, PTEN, PI3K-Akt-mTOR and MAPK signaling in cancer. Therefore, a better understanding of the intricate relationships between mitochondrial ROS and autophagy may ultimately allow cancer biologists to harness mitochondrial ROS-mediated autophagic pathways for cancer drug discovery. Copyright © 2011 Elsevier Inc. All rights reserved.

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AMP-activated protein kinase, stress responses and cardiovascular diseases.

Shaobin Wang, Hui Zou, Jin-Ping Song (2012)

AMPK (AMP-activated protein kinase) is one of the key players in maintaining intracellular homoeostasis. AMPK is well known as an energy sensor and can be activated by increased intracellular AMP levels. Generally, the activation of AMPK turns on catabolic pathways that generate ATP, while inhibiting cell proliferation and biosynthetic processes that consume ATP. In recent years, intensive investigations on the regulation and the function of AMPK indicates that AMPK not only functions as an intracellular energy sensor and regulator, but is also a general stress sensor that is important in maintaining intracellular homoeostasis during many kinds of stress challenges. In the present paper, we will review recent literature showing that AMPK functions far beyond its proposed energy sensor and regulator function. AMPK regulates ROS (reactive oxygen species)/redox balance, autophagy, cell proliferation, cell apoptosis, cellular polarity, mitochondrial function and genotoxic response, either directly or indirectly via numerous downstream pathways under physiological and pathological conditions.

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Author and article information

Journal

Journal ID (nlm-ta): Oncol Lett

Journal ID (iso-abbrev): Oncol Lett

Journal ID (publisher-id): OL

Title: Oncology Letters

Publisher: D.A. Spandidos

ISSN (Print): 1792-1074

ISSN (Electronic): 1792-1082

Publication date (Print): May 2013

Publication date (Electronic): 22 February 2013

Publication date PMC-release: 22 February 2013

Volume: 5

Issue: 5

Pages: 1541-1545

Affiliations

[1 ]Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei Medical University, Taipei 11696;

[2 ]Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11696;

[3 ]Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696;

[4 ]Center of Excellence for Cancer Research, Taipei Medical University, Taipei 11696;

[5 ]Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696;

[6 ]National Institutes of Cancer Research, National Health Research Institutes, Miaoli 35053;

[7 ]Division of Hematology and Medical Oncology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan, R.O.C.

[8 ]Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11696, Taiwan, R.O.C.

Author notes

Correspondence to: Dr Liang-Ming Lee, Department of Urology, Wan Fang Hospital, Taipei Medical University, 111 Sec. 3 Xinglong Road, Taipei 11696, Taiwan, R.O.C., E-mail: lm@ 123456tmu.edu.tw

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Publisher ID: ol-05-05-1541

DOI: 10.3892/ol.2013.1211

PMC ID: 3678889

PubMed ID: 23760395

SO-VID: 12766874-4f76-496a-8d47-81136be02542

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This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

Mefloquine exerts anticancer activity in prostate cancer cells via ROS-mediated modulation of Akt, ERK, JNK and AMPK signaling

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Karger: Oncology

Most cited references 26

Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial.

Mitochondrial ROS generation for regulation of autophagic pathways in cancer.

AMP-activated protein kinase, stress responses and cardiovascular diseases.

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