Repositioning chloroquine and metformin to eliminate cancer stem cell traits in pre-malignant lesions

• Published in: Drug resistance updates Vol. 14; no. 4; pp. 212 - 223
• Main Authors: Vazquez-Martin, Alejandro, López-Bonetc, Eugeni, Cufí, Sílvia, Oliveras-Ferraros, Cristina, Del Barco, Sonia, Martin-Castillo, Begoña, Menendez, Javier A
• Format: Journal Article
• Language: English
• Published: Scotland Elsevier Ltd 01.08.2011
• Subjects: Aging - pathology; Aging - physiology; Animals; Antimalarials - pharmacology; Antimalarials - therapeutic use; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Autophagy; Autophagy - genetics; Autophagy - physiology; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - physiopathology; Breast Neoplasms - prevention & control; Cancer stem cells; Carcinoma, Intraductal, Noninfiltrating - drug therapy; Carcinoma, Intraductal, Noninfiltrating - prevention & control; Chloroquine - pharmacology; Chloroquine - therapeutic use; DCIS; Drug Evaluation, Preclinical; Drug Repositioning; EMT; Epithelial-Mesenchymal Transition - drug effects; Epithelial-Mesenchymal Transition - genetics; Epithelial-Mesenchymal Transition - physiology; Female; Hematology, Oncology and Palliative Medicine; Humans; Hypoglycemic Agents - pharmacology; Hypoxia; Infectious Disease; Metformin - pharmacology; Metformin - therapeutic use; Molecular Targeted Therapy; Neoplasms - pathology; Neoplasms - prevention & control; Neoplastic Stem Cells - pathology; Neoplastic Stem Cells - physiology; OIS; Oncogene-induced senescence; Phenotype; Signal Transduction; TGF-beta Superfamily Proteins - agonists; DCIS; OIS; Hypoxia; Breast cancer; Cancer stem cells; Oncogene-induced senescence; Autophagy; EMT
• ISSN: 1368-7646; 1532-2084
• DOI: 10.1016/j.drup.2011.04.003

Abstract Ideal oncology drugs would be curative after a short treatment course if they could eliminate epithelium-originated carcinomas at their non-invasive, pre-malignant stages. Such ideal molecules, which are expected to molecularly abrogate all the instrumental mechanisms acquired by migrating cancer stem cells (CSCs) to by-pass tumour suppressor barriers, might already exist. We here illustrate how system biology strategies for repositioning existing FDA-approved drugs may accelerate our therapeutic capacity to eliminate CSC traits in pre-invasive intraepithelial neoplasias. First, we describe a signalling network signature that overrides bioenergetics stress- and oncogene-induced senescence (OIS) phenomena in CSCs residing at pre-invasive lesions. Second, we functionally map the anti-malarial chloroquine and the anti-diabetic metformin (“old drugs”) to their recently recognized CSC targets (“new uses”) within the network. By discussing the preclinical efficacy of chloroquine and metformin to inhibiting the genesis and self-renewal of CSCs we finally underscore the expected translational impact of the “old drugs–new uses” repurposing strategy to open a new CSC-targeted chemoprevention era.