Inhibition of telomerase activity preferentially targets aldehyde dehydrogenase-positive cancer stem-like cells in lung cancer

• Published in: Molecular cancer Vol. 10; no. 1; p. 96
• Main Authors: Serrano, Diego, Bleau, Anne-Marie, Fernandez-Garcia, Ignacio, Fernandez-Marcelo, Tamara, Iniesta, Pilar, Ortiz-de-Solorzano, Carlos, Calvo, Alfonso
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 09.08.2011; BioMed Central; BMC
• Subjects: Aldehyde Dehydrogenase - metabolism; ALDH activity; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Benzamides - pharmacology; Benzamides - therapeutic use; cancer stem cells; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Care and treatment; Cell Line, Tumor; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Genetic aspects; Health aspects; Humans; Lung cancer; Lung cancer, Non-small cell; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Male; Mice; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; Molecular Targeted Therapy; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Neoplastic Stem Cells - physiology; Oxidoreductases; Physiological aspects; Reverse transcriptase inhibitors; telomerase; Telomerase - antagonists & inhibitors; Xenograft Model Antitumor Assays; Spain
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/1476-4598-10-96

Mortality rates for advanced lung cancer have not declined for decades, even with the implementation of novel chemotherapeutic regimens or the use of tyrosine kinase inhibitors. Cancer Stem Cells (CSCs) are thought to be responsible for resistance to chemo/radiotherapy. Therefore, targeting CSCs with novel compounds may be an effective approach to reduce lung tumor growth and metastasis. We have isolated and characterized CSCs from non-small cell lung cancer (NSCLC) cell lines and measured their telomerase activity, telomere length, and sensitivity to the novel telomerase inhibitor MST312. The aldehyde dehydrogenase (ALDH) positive lung cancer cell fraction is enriched in markers of stemness and endowed with stem cell properties. ALDH+ CSCs display longer telomeres than the non-CSC population. Interestingly, MST312 has a strong antiproliferative effect on lung CSCs and induces p21, p27 and apoptosis in the whole tumor population. MST312 acts through activation of the ATM/pH2AX DNA damage pathway (short-term effect) and through decrease in telomere length (long-term effect). Administration of this telomerase inhibitor (40 mg/kg) in the H460 xenograft model results in significant tumor shrinkage (70% reduction, compared to controls). Combination therapy consisting of irradiation (10Gy) plus administration of MST312 did not improve the therapeutic efficacy of the telomerase inhibitor alone. Treatment with MST312 reduces significantly the number of ALDH+ CSCs and their telomeric length in vivo. We conclude that antitelomeric therapy using MST312 mainly targets lung CSCs and may represent a novel approach for effective treatment of lung cancer.