title: RL66 a second-generation curcumin analog has potent in vivo and in vitro             anticancer activity in ER‑negative breast cancer models.
abstract: There is a need for the development of new safe and efficacious drug therapies             for the treatment of estrogen receptor (ER)‑negative breast cancers. 1-Methyl-3,5-bis[(E)-4-pyridyl)methylidene]-4-piperidone             (RL66) is a second generation curcumin analog that exhibits potent cytotoxicity             towards a variety of ER-negative breast cancer cells. Therefore, we have further             examined the mechanism of this novel drug in in vitro and in vivo models of ER-negative             breast cancer. The mechanistic studies demonstrated that RL66 (2 µM) induced cell             cycle arrest in the G2/M phase of the cell cycle. Moreover, RL66 (2 µM) caused             40% of SKBr3 cells to undergo apoptosis after 48 h and this effect was time-dependent.             This correlated with an increase in cleaved caspase-3 as shown by western blot             analysis. RL66 (2 µM) also decreased HER2/neu phosphorylation and increased p27             in SKBr3 cells, while in MDA-MB-231 and MDA-MB-468 cells RL66 (2 µM) significantly             decreased Akt phosphorylation and transiently increased the stress kinases JNK1/2             and MAPK p38. In addition, RL66 exhibited anti-angiogenic potential in vitro as             it inhibited HUVEC cell migration 46% and the ability of these cells to form tube‑like             networks. RL66 (8.5 mg/kg) suppressed the growth of MDA-MB-468 xenograft tumors             by 48% compared to vehicle control following 10 weeks of daily oral administration.             Microvessel density in the tumors from treated mice was also decreased 57% compared             to control. Thus our findings demonstrate that RL66 has potent proapoptotic and             anti-angiogenic properties in vivo and in vitro and has the potential to be further             developed as a drug for the treatment of ER‑negative breast cancer.
authors.affiliation: Department of Pharmacology and Toxicology, University of Otago,                     Dunedin, New Zealand.
authors.forename: Babasaheb
authors.initials: B
authors.lastname: Yadav
authors.forename: Sebastien
authors.initials: S
authors.lastname: Taurin
authors.forename: Lesley
authors.initials: L
authors.lastname: Larsen
authors.forename: Rhonda J
authors.initials: RJ
authors.lastname: Rosengren
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D010881:Piperidones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010881:Piperidones; D011725:Pyridines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; C579034:1-methyl-3,5-bis((4-pyridyl)methylidene)-4-piperidone