Concurrent targeting of BMI1 and CDK4/6 abrogates tumor growth in vitro and in vivo.

Abstract

Despite recent advances in cancer management and therapy, resistance to cytotoxic medications remains a major clinical challenge; hence, combination-based anti-cancer treatment regimens are currently gaining momentum. PTC-209 reduced BMI1 protein expression, while palbociclib inhibited CDK4, Rb, and pRbSer795 protein expression in MDA-MB-231 cells. PTC-209 and palbociclib exhibited dose-dependent cytotoxic effects against MDA-MB-231 (breast), HCT116 (colon), and PC-3 (prostate) models, which was more profound in the combination group. Transcriptome and pathway analyses revealed inhibition of insulin signaling, focal adhesion, DNA damage response, and Wnt/pluripotency signaling pathways as well as cell proliferation, and cellular movement functional categories by PTC-209. Transcriptome and pathway analyses revealed palbociclib to mainly affect cell cycle progression and survival. Upstream analysis identified several networks affected by PTC-209 (EZH2, IFNB1, TRIB3, EGFR, SREBF1, IL1A, ERG, TGFB1, MAX, MNT) and palbociclib (RABL6, MITF, RARA, TAL1, AREG, E2F3, FOXM1, ESR1, ERBB2, and E2F). PTC-209 and palbociclib reduced colony and sphere formation, cell migration, and cell viability, which was further enhanced in the combination group. Concordantly, combination of PTC-209 and palbociclib exhibited more profound effects on MDA-MB-231 tumor formation in vivo. Our data suggest concurrent targeting of BMI1 and CDK4/CDK6 might provide novel therapeutic opportunity for breast, colon, and prostate cancer.

• Authors: Ramesh Elango, Radhakrishnan Vishnubalaji, Muthurangan Manikandan, Sarah Ibrahim Binhamdan, Abdul-Aziz Siyal, Yasser A Alshawakir, Musaad Alfayez, Abdullah Aldahmash, Nehad M Alajez
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 13696 (09 23 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31548560 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Heterocyclic Compounds, 2-Ring
• PTC-209
• Piperazines
• Protein Kinase Inhibitors
• Pyridines
• Thiazoles
• Cyclin-Dependent Kinase 4
• Cyclin-Dependent Kinase 6
• MAPK7 protein, human
• Mitogen-Activated Protein Kinase 7
• palbociclib

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cyclin-Dependent Kinase 4 (metabolism)
• Cyclin-Dependent Kinase 6 (metabolism)
• Heterocyclic Compounds, 2-Ring (pharmacology)
• Humans
• Mitogen-Activated Protein Kinase 7 (metabolism)
• Piperazines (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Pyridines (pharmacology)
• Thiazoles (pharmacology)