title: Characterization of lovastatin-docosahexaenoate anticancer properties against breast cancer cells.
abstract: Lovastatin (LOV) and docosahexaenoic acid (DHA), besides improving cardiovascular functions, are also known for their anticancer activities. However, use of these compounds for treating or preventing cancer is limited because of their efficacies. The approach pursued involved chemical linkage of these two chemotypes. A lovastatin-docosahexaenoate (LOV-DHA) conjugate was prepared and tested against selected breast tumor cells lines with differential expression of estrogen receptors (ER) and Heregulin-2 (Her-2). The LOV-DHA conjugate exhibited superior cytotoxic effects against ER(-)/Her-2(-) cell lines (MDA-MB-231 and MDA-MB-468), which were not observed with DHA or lovastatin alone, or in combination. Lovastatin supplementation arrested cells in the G₀/G₁ phase and enhanced expression levels of p21, whereas the conjugate did not demonstrate cell cycle arrest nor increased p21 expression. The LOV-DHA conjugate induced significant (P<0.05) apoptosis as low as 1 μM, whereas DHA and lovastatin were ineffective at this concentration. The growth inhibitory effects of lovastatin were reversed by the addition of mevalonate, whereas mevalonate had no effect on the LOV-DHA conjugate-induced growth inhibition in MDA-MB-231 cells. Furthermore, the LOV-DHA conjugates were stable in mouse serum and intracellularly in MDA-MB-231 cells. These data suggest that the LOV-DHA conjugate mediated its effects through a HMG-CoA reductase-independent pathway and exerted significantly (P<0.05) higher anticancer effects in breast cancer cells than lovastatin or DHA alone.
authors.affiliation: Cellular Biochemistry Laboratory, Methodist Research Institute, Indiana University Health, 1800 N. Capitol Ave., Room E504, Indianapolis, IN 46202, USA; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: rsiddiqu@iuhealth.org.
authors.forename: Rafat A
authors.initials: RA
authors.lastname: Siddiqui
authors.affiliation: Cellular Biochemistry Laboratory, Methodist Research Institute, Indiana University Health, 1800 N. Capitol Ave., Room E504, Indianapolis, IN 46202, USA.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Harvey
authors.affiliation: Cellular Biochemistry Laboratory, Methodist Research Institute, Indiana University Health, 1800 N. Capitol Ave., Room E504, Indianapolis, IN 46202, USA.
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Cellular Biochemistry Laboratory, Methodist Research Institute, Indiana University Health, 1800 N. Capitol Ave., Room E504, Indianapolis, IN 46202, USA.
authors.forename: Selvamuthu K
authors.initials: SK
authors.lastname: Natarajan
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, 575 Stadium Mall Dr, West Lafayette, IN 47907, USA.
authors.forename: V Jo
authors.initials: VJ
authors.lastname: Davisson
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008148:Lovastatin / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004281:Docosahexaenoic Acids; D008148:Lovastatin
keywords: Breast cancer; Docosahexaenoic acid; Lipid–drug conjugates; Lovastatin