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

Abstract

BACKGROUND:

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.

RESULTS:

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.

CONCLUSIONS:

We conclude that antitelomeric therapy using MST312 mainly targets lung CSCs and may represent a novel approach for effective treatment of lung cancer.

• Authors: Diego Serrano, Anne-Marie Bleau, Ignacio Fernandez-Garcia, Tamara Fernandez-Marcelo, Pilar Iniesta, Carlos Ortiz-de-Solorzano, Alfonso Calvo
• Journal: Molecular cancer (Mol Cancer) Vol. 10 Pg. 96 (Aug 09 2011) ISSN: 1476-4598 [Electronic] England
• PMID: 21827695 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzamides
• Enzyme Inhibitors
• MST 312
• Aldehyde Dehydrogenase
• Telomerase

Topics

• Aldehyde Dehydrogenase (metabolism)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Benzamides (pharmacology, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Cell Line, Tumor
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Humans
• Lung Neoplasms (drug therapy, pathology)
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Mice, Transgenic
• Molecular Targeted Therapy
• Neoplastic Stem Cells (drug effects, metabolism, pathology, physiology)
• Telomerase (antagonists & inhibitors)
• Xenograft Model Antitumor Assays