Thiacremonone augments chemotherapeutic agent-induced growth inhibition in human colon cancer cells through inactivation of nuclear factor-{kappa}B.
Chemotherapeutic strategies commonly use multiple agents to overcome drug resistance and to lower drug toxicity. Activation of nuclear factor-kappaB (NF-kappaB) is implicated in drug resistance in cancer cells. Previously, we reported that thiacremonone, a novel sulfur compound isolated from garlic, inhibited NF-kappaB and cancer cell growth with IC(50) values about 100 microg/mL in colon cancer cells. In the present study, we tested whether thiacremonone could increase susceptibility of cancer cells to chemotherapeutics through inactivation of NF-kappaB. Colon cancer cells were cotreated with thiacremonone (50 microg/mL, half dose of IC(50)) and lower doses of each chemotherapeutic agent (half dose of IC(50)) for 24 hours. NF-kappaB activity was completely abrogated in cells treated with a combination of thiacremonone and docetaxel, whereas thiacremonone on its own did not alter NF-kappaB activity. This combined drug effect was also found with other anticancer drugs in colon cancer and in other cancer cells. In good correlation with inhibition of cell growth and NF-kappaB activity, the combination treatment also regulated NF-kappaB target genes. Oral treatment of mice with thiacremonone (1 mg/kg) by administering it in drinking water for 4 weeks significantly augmented docetaxel (1 mg/kg, i.p., four times)-induced decrease of tumor growth accompanied with regulation of NF-kappaB activity and NF-kappaB target genes. These results warrant carefully designed clinical studies investigating the combination of thiacremonone and commonly used chemotherapeutic agents for the treatment of human cancers.
Ban
Jung Ok
JO
Medical Research Center, ChungbukNational University, Chungbuk, Korea.
Lee
Hee Soon
HS
Jeong
Heon-Sang
HS
Song
Sugkil
S
Hwang
Bang Yeon
BY
Moon
Dong Cheul
DC
Yoon
Do Young
DY
Han
Sang Bae
SB
Hong
Jin Tae
JT
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077143:Docetaxel; D004334:Drug Administration Schedule; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage / Q000494:pharmacology*; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D051017:Apoptosis Regulatory Proteins; D016328:NF-kappa B; D043823:Taxoids; D013876:Thiophenes; C524083:thiacremonone; D000077143:Docetaxel