In vitro therapeutic effects of abemaciclib on triple‐negative breast cancer cells

Abstract

The cyclin-dependent kinases 4 and 6 have led to a significant improvement in the treatment of hormone-receptor-positive breast cancer. However, the therapeutic potential of abemaciclib in triple-negative breast cancer (TNBC) has not been definitively elucidated. Therefore, the objective of this study was to investigate abemaciclib mediated antiproliferative effects on MDA-MB-231 and MDA-MB-468 TNBC and MCF-10A cell line through annexin V, cell cycle, caspase-3, reverse transcription-polymerase chain reaction analysis, acridine orange, and DAPI staining, for the first time. In addition, the autophagy-related cell death was assessed by autophagy-LC3 assay and acidic vesicular organelles staining. Our findings demonstrated that abemaciclib treatment resulted in significant apoptotic cell death in TNBC cells via G0/G1 arrest, chromatin condensation, the upregulation of caspase-3 and Bax levels, and the downregulation of Bcl-2. However, the formation of a large number of cytoplasmic vacuoles was not associated with autophagy. Therefore, abemaciclib treatment could be an effective treatment for TNBC. However, further studies are needed to elucidate the molecular mechanism of abemaciclib-induced apoptotic as well as atypical cell death derived from lysosomes in TNBC.

Cellular senescence triggers intracellular acidification and lysosomal pH alkalinized via ATP6AP2 attenuation in breast cancer cells

“…Doxo is a widely used chemotherapeutic agent that exerts anticancer effects and induces cellular senescence in different cell types and mouse models [54][55][56][57][58][59] . Abe causes cell cycle arrest and reduces cell proliferation by inhibiting CDK4/6, thereby contributing to senescence [60][61][62] . Stable cellular senescence was induced in MDA-MB-231 and MCF-7 cells using Doxo and Abe.…”

Recent Advances in Drug Discovery for Triple-Negative Breast Cancer Treatment

“…Recently, Sekeroglu et al demonstrated that abemaciclib caused significant apoptosis in TNBC cells via G0/G1 arrest, chromatin condensation, the upregulation of caspase-3 and Bax levels, and the downregulation of Bcl-2. The formation of a large number of cytoplasmic vacuoles not associated with autophagy suggested that treatment with 16 could be effective for TNBC [92] (Figure 3).…”

Cyclin‐dependent kinase inhibitors enhance programmed cell death protein 1 immune checkpoint blockade efficacy in triple‐negative breast cancer by affecting the immune microenvironment

“…Extensive preclinical research has validated the mechanisms by which CDK4/6 inhibition promotes CD8 T cell memory formation, regulates PD‐L1 protein expression, and alters the tumor immune microenvironment 13 . Preliminary studies by Ozman et al 14 . and Peng et al 15 .…”

“…12 Extensive preclinical research has validated the mechanisms by which CDK4/6 inhibition promotes CD8 T cell memory formation, regulates PD-L1 protein expression, and alters the tumor immune microenvironment. 13 Preliminary studies by Ozman et al 14 and Peng et al 15 have also identified the potential antitumor effects of abemaciclib in triplenegative breast cancer (TNBC). Two ongoing clinical trials (NCT03979508 and NCT01042379) are recruiting TNBC patients for investigation involving abemaciclib.…”