Experimental therapy for colon cancer: anti-cancer effects of TLR9 agonism, combination with other therapeutic modalities, and dependence upon p53.
The present study demonstrates the efficacy of utilizing TLR9 (toll-like receptor 9) agonism as a potential therapy for colon cancer. We examined the effects of two types of TLR9 agonists: a traditional CpG oligonucleotide and a novel immunomodulatory oligonucleotide in models of colon cancer, both alone and in combination with conventional cancer therapies. Because the tumor suppressor p53 is involved in many anti-cancer pathways, and is mutated in more than 50% of cancers, we determined whether p53 is necessary for the anti-tumor effects observed following treatment with TLR9 agonists. We also established that colon cancer cells express TLR9, which has not been demonstrated previously. The effects of TLR9 agonism on the growth, proliferation and apoptosis of colon cancer cells in vitro was then examined. We report five major discoveries: i) TLR9 agonism results in significant activity in models of colon cancer, ii) TLR9 agonists increase the anti-tumor effects of radiation and chemotherapy, iii) p53 is not required for the anti-cancer effects of TLR9 agonism, iv) human colon cancer cells express TLR9, and v) TLR9 agonism leads to decreased cell survival and proliferation and induces apoptosis of colon cancer cells in vitro. These results provide a basis for future studies determining the potential of utilizing TLR9 agonists for human colon cancer therapy.
Rayburn
Elizabeth R
ER
Department of Pharmacology and Toxicology, Division of Clinical Pharmacology, University of Alabama at Birmingham, Birmingham, AL, USA.
Wang
Wei
W
Zhang
Ruiwen
R
Wang
Hui
H
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018899:CpG Islands; D005260:Female; D006801:Humans; D051379:Mice; D009841:Oligonucleotides / Q000627:therapeutic use*; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D000970:Antineoplastic Agents; D009841:Oligonucleotides; D051217:Toll-Like Receptor 9; D016159:Tumor Suppressor Protein p53