RL71, a second-generation curcumin analog, induces apoptosis and downregulates             Akt in ER-negative breast cancer cells.
There is a need for the development of new, safe and efficacious drug therapies for the treatment of estrogen receptor (ER)-negative breast cancers. RL71 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 anticancer activity in three different ER-negative breast cancer cell lines. The mechanistic studies demonstrated that RL71 (1 µM) induced cell cycle arrest in the G2/M phase of the cell cycle. Moreover, RL71 (1 µM) caused 35% 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 blotting. RL71 (1 µM) also decreased HER2/neu phosphorylation and increased p27 in SKBr3 cells. While in MDA-MB-231 and MDA-MB-468 cells RL71 (1 µM) significantly decreased Akt phosphorylation and transiently increased the stress kinases JNK1/2 and p38 MAPK. In addition, RL71 exhibited anti-angiogenic potential in vitro as it inhibited HUVEC cell migration and the ability of these cells to form tube-like networks. RL71 (8.5 mg/kg) was also orally bioavailable as it produced a peak plasma concentration of 0.405 µg/ml, 5 min after oral drug administration. Thus, our findings provide evidence that RL71 has potent anticancer activity and has potential to be further developed as a drug for the treatment of ER-negative breast cancer.
Department of Pharmacology and Toxicology, University of Otago,                     Dunedin, New Zealand.
Babasaheb
B
Yadav
Sebastien
S
Taurin
Lesley
L
Larsen
Rhonda J
RJ
Rosengren
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D053148:Caspase 3 / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D036381:Diarylheptanoids; D015536:Down-Regulation; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D051379:Mice; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis
D000970:Antineoplastic Agents; D053148:Caspase 3; D003474:Curcumin; D036381:Diarylheptanoids; D048031:JNK Mitogen-Activated Protein Kinases; D018809:Proliferating Cell Nuclear Antigen; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D048051:p38 Mitogen-Activated Protein Kinases; C577607:3,5-bis(3,4,5-trimethoxybenzylidene)-1-methylpiperidine-4-one; C413374:p27 antigen; C508053:ERBB2 protein, human