title: Mcl-1 antagonism is a potential therapeutic strategy in a subset of solid cancers.
abstract: Cancer cell survival is frequently dependent on the elevated levels of members of the Bcl-2 family of prosurvival proteins that bind to and inactivate BH3-domain pro-apoptotic cellular proteins. Small molecules that inhibit the protein-protein interactions between prosurvival and proapoptotic Bcl-2 family members (so-called "BH3 mimetics") have a potential therapeutic value, as indicated by clinical findings obtained with ABT-263 (navitoclax), a Bcl-2/Bcl-xL antagonist, and more recently with GDC-0199/ABT-199, a more selective antagonist of Bcl-2. Here, we report study results of the functional role of the prosurvival protein Mcl-1 against a panel of solid cancer cell lines representative of different tumor types. We observed silencing of Mcl-1 expression by small interfering RNAs (siRNAs) significantly reduced viability and induced apoptosis in almost 30% of cell lines tested, including lung and breast adenocarcinoma, as well as glioblastoma derived lines. Most importantly, we provide a mechanistic basis for this sensitivity by showing antagonism of Mcl-1 function with specific BH3 peptides against isolated mitochondria induces Bak oligomerization and cytochrome c release, therefore demonstrating that mitochondria from Mcl-1-sensitive cells depend on Mcl-1 for their integrity and that antagonizing Mcl-1 function is sufficient to induce apoptosis. Thus, our results lend further support for considering Mcl-1 as a therapeutic target in a number of solid cancers and support the rationale for development of small molecule BH3-mimetics antagonists of this protein.
authors.affiliation: Nerviano Medical Sciences S.r.l. - Oncology, Viale Pasteur 10, I-20014 Nerviano, Milan, Italy. Electronic address: michele.modugno@nervianoms.com.
authors.forename: Michele
authors.initials: M
authors.lastname: Modugno
authors.affiliation: Nerviano Medical Sciences S.r.l. - Oncology, Viale Pasteur 10, I-20014 Nerviano, Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Banfi
authors.affiliation: Nerviano Medical Sciences S.r.l. - Oncology, Viale Pasteur 10, I-20014 Nerviano, Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Gasparri
authors.affiliation: Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Borzilleri
authors.affiliation: Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: Percy
authors.initials: P
authors.lastname: Carter
authors.affiliation: Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: Lyndon
authors.initials: L
authors.lastname: Cornelius
authors.affiliation: Janssen, Pharmaceutical Companies of Johnson and Johnson, 1400 McKean Rd, Spring House, Ambler, PA 19002, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Gottardis
authors.affiliation: Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: Ving
authors.initials: V
authors.lastname: Lee
authors.affiliation: Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Mapelli
authors.affiliation: Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Naglich
authors.affiliation: Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Tebben
authors.affiliation: Bristol-Myers Squibb Research, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Vite
authors.affiliation: Nerviano Medical Sciences S.r.l. - Oncology, Viale Pasteur 10, I-20014 Nerviano, Milan, Italy.
authors.forename: Wilma
authors.initials: W
authors.lastname: Pastori
authors.affiliation: Nerviano Medical Sciences S.r.l. - Oncology, Viale Pasteur 10, I-20014 Nerviano, Milan, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: Albanese
authors.affiliation: Nerviano Medical Sciences S.r.l. - Oncology, Viale Pasteur 10, I-20014 Nerviano, Milan, Italy.
authors.forename: Emiliana
authors.initials: E
authors.lastname: Corti
authors.affiliation: Nerviano Medical Sciences S.r.l. - Oncology, Viale Pasteur 10, I-20014 Nerviano, Milan, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Ballinari
authors.affiliation: Nerviano Medical Sciences S.r.l. - Oncology, Viale Pasteur 10, I-20014 Nerviano, Milan, Italy.
authors.forename: Arturo
authors.initials: A
authors.lastname: Galvani
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering
keywords: Apoptosis; Cancer; Mcl-1; Mitochondria; SiRNA