title: The plant alkaloid and anti-leukemia drug homoharringtonine sensitizes resistant human colorectal carcinoma cells to TRAIL-induced apoptosis via multiple mechanisms.
abstract: 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.
authors: Department of Cell Signaling & Apoptosis, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Vídeňská 1083, 14220 Praha 4, Czech Republic.
authors: Lenka
authors: L
authors: Beranova
authors: Antonio R
authors: AR
authors: Pombinho
authors: Jarmila
authors: J
authors: Spegarova
authors: Michal
authors: M
authors: Koc
authors: Magdalena
authors: M
authors: Klanova
authors: Jan
authors: J
authors: Molinsky
authors: Pavel
authors: P
authors: Klener
authors: Petr
authors: P
authors: Bartunek
authors: Ladislav
authors: L
authors: Andera
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D019073:HT29 Cells; D006248:Harringtonines / Q000494:pharmacology*; D000077863:Homoharringtonine; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014183:Transplantation, Heterologous
chemical_list: D051017:Apoptosis Regulatory Proteins; D006248:Harringtonines; D053221:TNF-Related Apoptosis-Inducing Ligand; D000077863:Homoharringtonine