The mechanistic effects of the dioxonaphthoimidazolium analog YM155 in renal cell carcinoma cell cycling and apoptosis.

Abstract

AIM:

To investigate the effect of dioxonaphthoimidazolium analog YM155 on cell cycle progression of the clear-cell variant of renal cell carcinoma (ccRCC).

MAIN METHODS:

Cell cycle analysis was performed using bromodeoxyuridine (BrdU) and PI, apoptosis initiation was monitored using Annexin V and proteins expression was determined using western immunoblotting.

KEY FINDINGS:

Here, we showed that YM155 activated stress-related molecules (histone H2AX, checkpoint kinases Chk1 and Chk2, p53) that mediate DNA damage checkpoint responses. The coordinated activation of these effector molecules disrupts progression of the cell cycle at the S phase as deduced from BrdU pulsing experiments and the ensuing changes in the levels of proteins (cyclins, CDKs, CDK inhibitors, phosphatases) that control cell cycle progression. Notably, we found increases in cyclin E and Cdc2 which regulate transition of cells from G1 to S, even as losses were observed for other CDKs and their cyclin partners. Furthermore, by inducing a loss in total pRb possibly by promoting its degradation, YM155 promoted the E2F transcription of genes that regulate entry into the S phase. After 24 h, cell cycle arrest to repair YM155-inflicted DNA damage was overtaken by p53-mediated apoptosis. YM155 induced increases in pro-apoptotic proteins (Bax and Bad), diminished anti-apoptotic proteins (Mcl-1, Bcl-xl, XIAP, survivin) and initiated cleavage of apoptotic marker proteins caspase 3 and PARP.

SIGNIFICANCE:

Taken together, the added insight provided on the cell cycle perturbative effects of YM155 may assist clinicians in framing rational choices for combining YM155 with other anti-cancer drugs or treatment modalities in ccRCC.

• Authors: Mei Yi Sim, Mei Lin Go, John Shyi Peng Yuen
• Journal: Life sciences (Life Sci) Vol. 203 Pg. 282-290 (Jun 15 2018) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 29689274 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Cell Cycle Proteins
• Imidazoles
• Naphthoquinones
• sepantronium

Topics

• Apoptosis (drug effects)
• Carcinoma, Renal Cell (drug therapy, metabolism, pathology)
• Cell Cycle (drug effects)
• Cell Cycle Proteins (metabolism)
• Cell Proliferation (drug effects)
• Humans
• Imidazoles (pharmacology)
• Kidney Neoplasms (drug therapy, metabolism, pathology)
• Naphthoquinones (pharmacology)
• Tumor Cells, Cultured