title: Methyl 3-hydroxyimino-11-oxoolean-12-en-28-oate (HIMOXOL), a synthetic oleanolic acid derivative, induces both apoptosis and autophagy in MDA-MB-231 breast cancer cells.
abstract: HIMOXOL (methyl 3-hydroxyimino-11-oxoolean-12-en-28-oate) is a synthetic derivative of oleanolic acid (OA). HIMOXOL revealed the highest cytotoxic effect among tested synthetic OA analogs. In this study we focused on elucidating the cytotoxic mechanism of HIMOXOL in MDA-MB-231 breast cancer cells. HIMOXOL reduced MDA-MB-231 cell viability with an IC50 value of 21.08±0.24μM. In contrast to OA, the tested compound induced cell death by activating apoptosis and the autophagy pathways. More specifically, we found that HIMOXOL was able to activate the extrinsic apoptotic pathway, which was proven by observation of caspase-8, caspase-3 and PARP-1 protein activation in Western blot analysis. An increase in the ratio of Bax/Bcl-2 protein levels was also detected. Moreover, HIMOXOL triggered microtubule-associated protein LC3-II expression and upregulated beclin 1. This observed compound activity was modulated by mitogen-activated protein kinases and NFκB/p53 signaling pathways. Together, these data suggest that HIMOXOL, a synthetic oleanolic acid derivative which activates dual cell death machineries, could be a potential and novel chemotherapeutic agent.
authors.affiliation: Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Przybyszewskiego 49 St., 60-355 Poznan, Poland. Electronic address: nszyman@ump.edu.pl.
authors.forename: Natalia
authors.initials: N
authors.lastname: Lisiak
authors.affiliation: Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Przybyszewskiego 49 St., 60-355 Poznan, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Paszel-Jaworska
authors.affiliation: Department of Organic Chemistry, Poznan University of Medical Sciences, Grunwaldzka 6 St., 60-780 Poznan, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bednarczyk-Cwynar
authors.affiliation: Department of Organic Chemistry, Poznan University of Medical Sciences, Grunwaldzka 6 St., 60-780 Poznan, Poland.
authors.forename: Lucjusz
authors.initials: L
authors.lastname: Zaprutko
authors.affiliation: Department of Clinical Immunology, Poznan University of Medical Sciences, Rokietnicka 5D St., 60-806 Poznan, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Kaczmarek
authors.affiliation: Department of Clinical Chemistry and Molecular Diagnostics, Poznan University of Medical Sciences, Przybyszewskiego 49 St., 60-355 Poznan, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Rybczyńska
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D000071186:Beclin-1; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C477012:MAP1LC3A protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C587228:methyl 3-hydroxyimino-11-oxoolean-12-en-28-oate; D009828:Oleanolic Acid; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020928:Mitogen-Activated Protein Kinases; D053148:Caspase 3; D053181:Caspase 8
keywords: 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; Apoptosis; Autophagy; BECN 1; Breast cancer; CDDO; HIMOXOL; IC(50); MAP LC3β; MAPK; MDC; OA; UA; beclin 1; half maximal inhibitory concentration; methyl 3-hydroxyimino-11-oxoolean-12-en-28-oate; microtubule-associated protein light chain beta; mitogen-activated protein kinase; monodansylcadaverine; oleanolic acid; ursolic acid