Chemotherapy and chemosensitization of non-small cell lung cancer with a novel immunomodulatory oligonucleotide targeting Toll-like receptor 9.
Lung cancer is a leading cause of death world-wide and the long-term survival rate for lung cancer patients is one of the lowest for any cancer. New therapies are urgently needed. The present study was designed to evaluate an immunomodulatory oligonucleotide as a novel type of therapy for lung cancer. The in vivo effects of the immunomodulatory oligonucleotides were determined in four tumor models derived from human non-small cell lung cancer (NSCLC) cell lines (A549, H1299, H358, and H520), administered alone or in combination with conventional chemotherapeutic agents used to treat lung cancer. The in vitro effects of the immunomodulatory oligonucleotide on the growth, apoptosis, and proliferation of NSCLC cells were also determined. We also examined NSCLC cells for expression of Toll-like receptor 9 (TLR9), the receptor for the immunomodulatory oligonucleotide. We showed several important findings: (a) treatment with the immunomodulatory oligonucleotide led to potent antitumor effects, inhibiting tumor growth by at least 60% in all four in vivo models; (b) combination with the immunomodulatory oligonucleotide led to enhanced effects following treatment with gemcitabine or Alimta; (c) the immunomodulatory oligonucleotide increased apoptosis, decreased proliferation, and decreased survival in A549 cells in vitro; and (d) both TLR9 mRNA and protein were expressed in NSCLC cells. The immunomodulatory oligonucleotide has potent antitumor effects as monotherapy and in combination with conventional chemotherapeutic agents, and may act directly on NSCLC cells via TLR9. The present study provides a rationale for developing the immunomodulatory oligonucleotide for lung cancer therapy.
Wang
Hui
H
Department of Pharmacology and Toxicology, University of Alabama at Birmingham, 1670 University Boulevard, Birmingham, AL 35294-0019, USA.
Rayburn
Elizabeth R
ER
Wang
Wei
W
Kandimalla
Ekambar R
ER
Agrawal
Sudhir
S
Zhang
Ruiwen
R
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004361:Drug Tolerance; D005260:Female; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009841:Oligonucleotides / Q000627:therapeutic use*; D000068437:Pemetrexed; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D005971:Glutamates; D007155:Immunologic Factors; D009841:Oligonucleotides; D012333:RNA, Messenger; D051217:Toll-Like Receptor 9; D000068437:Pemetrexed; D003841:Deoxycytidine; D006147:Guanine; D000093542:Gemcitabine