Antiproliferative activity of the isoindigo 5'-Br in HL-60 cells is mediated by apoptosis, dysregulation of mitochondrial functions and arresting cell cycle at G0/G1 phase

Cancer Letters
Ayman M SalehSyed A A Rizvi

Abstract

Our new compound, 5'-Br [(E)-1-(5'-bromo-2'-oxoindolin-3'-ylidene)-6-ethyl-2,3,6,9-tetrahydro-2,9-dioxo-1H-pyrrolo[3,2-f]quinoline-8-carboxylic acid], had shown strong, selective antiproliferative activity against different cancer cell lines. Here, we aim to comprehensively characterize the mechanisms associated with its cytotoxicity in the human promyelocytic leukemia HL-60 cells. We focused at studying the involvement of apoptotic pathway and cell cycle effects. 5'-Br significantly inhibited proliferation by inducing caspase-dependent apoptosis. Involvement of caspase independent mechanism is also possible due to observed inability of z-VAD-FMK to rescue apoptotic cells. 5'-Br was found to trigger intrinsic apoptotic pathway as indicated by depolarization of the mitochondrial inner membrane, decreased level of cellular ATP, modulated expression and phosphorylation of Bcl-2 leading to loss of its association with Bax, and increased release of cytochrome c. 5'-Br treated cells were found arrested at G0/G1 phase with modulation in protein levels of cyclins, dependent kinases and their inhibitors. Expression and enzymatic activity of CDK2 and CDK4 was found inhibited. Retinoblastoma protein (Rb) phosphorylation was also inhibited...Continue Reading

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Citations

Nov 17, 2015·Journal of Photochemistry and Photobiology. B, Biology·Andrea V JuarezPatricia Pons
May 8, 2016·Apoptosis : an International Journal on Programmed Cell Death·Ayman M SalehSyed A Rizvi
Jan 12, 2017·Bioorganic & Medicinal Chemistry Letters·Yingyu ChenHaijun Chen
Mar 1, 2017·Beilstein Journal of Nanotechnology·Tatiana N PashirovaOleg G Sinyashin
Oct 14, 2017·Journal of Applied Toxicology : JAT·Basem M JaberAyman M Saleh

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