The plant alkaloid and anti-leukemia drug homoharringtonine sensitizes resistant human colorectal carcinoma cells to TRAIL-induced apoptosis via multiple mechanisms

0394700 - ÚMG 2013 RIV US eng J - Článek v odborném periodiku
Beranová, Lenka - Pombinho, António R. - Špegárová, Jarmila - Koc, Michal - Klánová, M. - Molinsky, J. - Klener, P. - Bartůněk, Petr - Anděra, Ladislav
The plant alkaloid and anti-leukemia drug homoharringtonine sensitizes resistant human colorectal carcinoma cells to TRAIL-induced apoptosis via multiple mechanisms.
Apoptosis. Roč. 18, č. 6 (2013), s. 739-750. ISSN 1360-8185. E-ISSN 1573-675X
Grant CEP: GA ČR GAP301/10/1971; GA MŠMT LH12202; GA MŠMT(CZ) LC06077; GA MZd(CZ) NT13201; GA MŠMT LM2011022
Grant ostatní: UK(CZ) P24/LF1/3; GA UK(CZ) 259211/110709; UK(CZ) UNCE 204021
Institucionální podpora: RVO:68378050
Klíčová slova: harringtonine * apoptosis * death receptor * cFLIP * Mcl-1
Kód oboru RIV: EB - Genetika a molekulární biologie
Impakt faktor: 3.614, rok: 2013

TNF-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic ligand from the TNF-alpha family that is under consideration, along with agonistic anti-TRAIL receptor antibodies, as a potential anti-tumor agent. However, most primary human tumors are resistant to monotherapy with TRAIL apoptogens, and thus the potential applicability of TRAIL in anti-tumor therapy ultimately depends on its rational combination with drugs targeting these resistances. In our high-throughput screening for novel agents/drugs that could sensitize TRAIL-resistant colorectal cancer cells to TRAIL-induced apoptosis, we found homoharringtonine (HHT), a cephalotaxus alkaloid and tested anti-leukemia drug, to be a very effective, low nanomolar enhancer of TRAIL-mediated apoptosis/growth suppression of these resistant cells. Co-treatment of TRAIL-resistant RKO or HT-29 cells with HHT and TRAIL led to the effective induction of apoptosis and the complete elimination of the treated cells. HHT suppressed the expression of the anti-apoptotic proteins Mcl-1 and cFLIP and enhanced the TRAIL-triggered activation of JNK and p38 kinases. The shRNA-mediated down-regulation of cFLIP or Mcl-1 in HT-29 or RKO cells variably enhanced their TRAIL-induced apoptosis but it did not markedly sensitize them to TRAIL-mediated growth suppression. However, with the notable exception of RKO/sh cFLIP cells, the downregulation of cFLIP or Mcl-1 significantly lowered the effective concentration of HHT in HHT + TRAIL co-treatment. Combined HHT + TRAIL therapy also led to the strong suppression of HT-29 tumors implanted into immunodeficient mice. Thus, HHT represents a very efficient enhancer of TRAIL-induced apoptosis with potential application in TRAIL-based, anti-cancer combination therapy.
Trvalý link: http://hdl.handle.net/11104/0222900