title: Anti-breast cancer effects of histone deacetylase inhibitors and calpain inhibitor.
abstract: Development of new breast cancer therapies is needed, particularly as cells become refractory or develop increased drug resistance. In an effort to develop such treatments, class I and II histone deacetylases (HDACs), alone and in combination with other cytotoxic agents, are currently in clinical trial. Herein, we discuss the effects of histone deacetylase inhibitors (HDACi) when used in combination with calpeptin, an inhibitor of the regulatory protease, calpain. We present results of study in two breast cancer cells lines with distinct characteristics: MDA-MB-231 and MCF-7. When used in combination with calpeptin, two chemically distinct HDACi significantly inhibited growth and increased cell death by inducing cell-cycle arrest and apoptosis. MCF-7 cells exhibited a greater proportion of arrest at the G(1) phase, whereas triple-negative MDA-MB-231 cells exhibited increased cell cycle arrest at the S phase. Methylation of the imprinted and silenced proapoptoic tumor suppressor gene aplasia Ras homolog member I (ARHI) was reduced in both cell lines after treatment with HDACi. However, it was only re-expressed on such treatment in MDA-MB-231 cells, suggesting that re-expression operates under differential mechanisms in these two cell lines. Collectively, these results showed that the combination of HDACi and calpeptin inhibited the growth of two distinctly different types of breast cancer cells and could have wide clinical applications, though the mechanisms of inhibition are possibly different.
authors: Cancer Center, Boston University School of Medicine, 72 East Concord Street, L-913, Boston, MA 02118, USA.
authors: Megan A
authors: MA
authors: Mataga
authors: Shoshana
authors: S
authors: Rosenthal
authors: Sarah
authors: S
authors: Heerboth
authors: Amrita
authors: A
authors: Devalapalli
authors: Shannon
authors: S
authors: Kokolus
authors: Leah R
authors: LR
authors: Evans
authors: McKenna
authors: M
authors: Longacre
authors: Genevieve
authors: G
authors: Housman
authors: Sibaji
authors: S
authors: Sarkar
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D005260:Female; D006023:Glycoproteins / Q000008:administration & dosage / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D011960:Receptors, Estrogen / Q000096:biosynthesis; D011980:Receptors, Progesterone / Q000096:biosynthesis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006023:Glycoproteins; D056572:Histone Deacetylase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C469745:LDLRAP1 protein, human; C039304:calpain inhibitors