A c-Met inhibitor increases the chemosensitivity of cancer stem cells to the irinotecan in gastric carcinoma

• Published in: British journal of cancer Vol. 109; no. 10; pp. 2619 - 2628
• Main Authors: Yashiro, M, Nishii, T, Hasegawa, T, Matsuzaki, T, Morisaki, T, Fukuoka, T, Hirakawa, K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12-11-2013; Nature Publishing Group
• Subjects: 692/699/67/1504/1829; 692/699/67/71; 692/700/565/1436/1437; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Antineoplastic Agents, Phytogenic - therapeutic use; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Camptothecin - analogs & derivatives; Camptothecin - pharmacology; Camptothecin - therapeutic use; Cancer Research; Cancer therapies; Chemotherapy; Drug Resistance; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Epidemiology; Gastric cancer; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Medical prognosis; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Oncology; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Response rates; Stem cells; Stomach Neoplasms - drug therapy; Stomach Neoplasms - pathology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Translational Therapeutics; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays; Japan; side population; irinotecan; cancer stem cell; gastric cancer; c-Met inhibitor; Antineoplastic agent; Stem cell; Stomach cancer; Stomach carcinoma; Isomerases; Cancerology; Topoisomerase I inhibitor; Tumor cell; Protooncogene; Gastric disease; Camptothecin derivatives; Human; Enzyme; DNA topoisomerase; Enzyme inhibitor; Increase; Malignant tumor; Irinotecan; C-Onc gene; Chemosensitivity; Digestive diseases; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2013.638

Background:
Cancer stem cells (CSCs) may be postulated mediators of the chemoresistance. This study aimed to determine an effective signal inhibitor with effects on the proliferation of CSCs in combination with anticancer drugs.
Methods:
We used three gastric cancer cell lines and three side population (SP)-enriched CSC cell lines. We examined the combined effects of inhibitors against stemness signals, including c-Met inhibitor SU11274, and five anticancer drugs on the CSC proliferation and mRNA expression of chemoresistance-associated genes.
Results:
The IC
50
of irinotecan in SP-enriched CSC was 10.5 times higher than parent OCUM-2M cells, whereas that of oxaliplatin, taxol, gemcitabine, and 5-fluorouracil was 2.0, 2.8, 2.0, and 1.2, respectively. The SP cell lines had higher expression levels of
UGT1A1
,
ABCG2
, and
ABCB1
than their parent cell lines. There was a synergistic antiproliferative effect with a combination of SU11274 and SN38 in SP cells, but not other inhibitors. The SU11274 significantly decreased the expression of
UGT1A1
, but not
ABCG2
and
ABCB1.
The SN38 plus SU11274 group more effectively suppressed
in vivo
tumour growth by OCUM-2M/SP cells than either group alone.
Conclusion:
Cancer stem cells have chemoresistance to irinotecan. The c-Met inhibitor may be a promising target molecule for irinotecan-based chemotherapy of gastric cancer.