INHIBITOR OF THE TRANSCRIPTION FACTOR NF-κB, DHMEQ, ENHANCES THE EFFECT OF PACLITAXEL ON CELLS OF ANAPLASTIC THYROID CARCINOMA IN VITRO AND IN VIVO.
Anticancer drug paclitaxel (Ptx) effect on biochemical mechanisms, regulating apoptosis in anaplas- tic thyroid carcinoma cells, was studied. It was shown that in addition to apoptotic cell death, Ptx induces signaling cascades that ensure cell survival. Paclitaxel-induced activation of nuclear factor kappa B (NF-κB) leads to an increase of some antiapoptotic proteins expression such as survivin, cIAP, XIAP. A novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), was found to enhance cytotoxic effect of Ptx in anaplastic thyroid carcinoma cells. An enhancement of caspase-3 and -9 activation and PARP cleavage as well as the decreased levels of proteins-inhibitors of apoptosis were observed when cells were treated with a combination of both drugs. Mitochondria transmembrane potential (Δψ (m)) loss was observed at higher concentrations of Ptx and DHMEQ. NF-κB inhibition also potentiates paclitaxel effect at tumors formed by xenotransplantation of FRO cells into mice. Tumor mass reduction, significantly different from the effects of each of the compounds alone, was observed in animals, treated with paclitaxel and NF-κB inhibitor. Thus, the combined use of paclitaxel and NF-κB inhibitor inhibits biochemical processes that contribute to the resistance of anaplastic thyroid carcinoma cells to paclitaxel action.
V V
VV
Pushkarev
D V
DV
Starenki
V M
VM
Pushkarev
O I
OI
Kovzun
M D
MD
Tronko
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003512:Cyclohexanones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D005260:Female; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D065646:Thyroid Carcinoma, Anaplastic / Q000188:drug therapy / Q000473:pathology; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D001549:Benzamides; D003512:Cyclohexanones; D016328:NF-kappa B; C464444:dehydroxymethylepoxyquinomicin; D017239:Paclitaxel