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Open AccessArticle
Synergistic Efficacy of CDK4/6 Inhibitor Abemaciclib and HDAC Inhibitor Panobinostat in Pancreatic Cancer Cells
by
Shraddha Bhutkar
Shraddha Bhutkar 1
,
Anjali Yadav
Anjali Yadav 1
,
Himaxi Patel
Himaxi Patel 1,
Shrikant Barot
Shrikant Barot 2,3
,
Ketan Patel
Ketan Patel
Ketan Patel, Ph.D., joined St. John’s University as an Assistant Professor of Pharmaceutical in of [...]
Ketan Patel, Ph.D., joined St. John’s University as an Assistant Professor of Pharmaceutical Sciences in September of 2016. He holds a Ph.D. in Pharmaceutics from the Institute of Chemical Technology, Mumbai, India (2013) and an M.Pharm. from Mumbai University, India (2009). Following the completion of his Ph.D., he joined the Department of Pharmaceutical Sciences at Florida A&M University as a postdoctoral fellow on a National Institutes of Health-funded research project on lung cancer. He has been awarded All India Council for Technical Education and University Grants Commission Special Assistance Programme fellowships. He has received a number of oral/poster/travelship awards for the presentation of his research at various international conferences, including those organized by the American Association of Pharmaceutical Scientists and the Controlled Release Society. Dr. Patel has authored more than 50 research publications in prestigious, peer-reviewed journals in the areas of pharmaceutics, 3D printing, opioid abuse deterrent formulation, the pre-exposure prophylaxis of HIV, and cancer nanotechnology. He has five US patents (three received and two pending) on innovative formulation technologies. Dr. Patel recently received a Melanoma Research Scholar Award from Outrun the Sun, Inc. and a National Institutes of Health grant for his research on the development of nanomedicine via proteolysis targeting chimera (PROTAC) for the treatment of metastatic melanoma.
1
and
Vikas V. Dukhande
Vikas V. Dukhande
Dr. Vikas Dukhande is an Associate Professor in Pharmacology at the Department of Pharmaceutical St. [...]
Dr. Vikas Dukhande is an Associate Professor in Pharmacology at the Department of Pharmaceutical Sciences, St. John's University. He is an external member of the Einstein-Mount Sinai Diabetes Research Center. He obtained his B.S. (Pharmacy) from ICT, Mumbai University, after which he worked for a year at Unilever Research India, where he screened natural actives that affected skin pigmentation. He then went on to earn his Ph.D. in Pharmacology from Idaho State University. Next, he joined Dr. Matthew Gentry’s lab as a postdoc in the Biochemistry Department at the College of Medicine at the University of Kentucky. Dr. Dukhande has received several grants and awards, including NIH grants to study glioblastoma and diabetes, an American Heart Association postdoctoral fellowship, a research presentation award and travel awards from ASPET. The unifying theme of the Dukhande lab's research is to elucidate the molecular mechanisms of cell death. His research aims to discover the intricate connections between cellular metabolism and cell death. Currently, the Dukhande lab is working on research projects to find treatments for cancers such as glioblastoma and pancreatic cancer. Another area of interest is the study of the molecular mechanisms of insulin resistance involved in metabolic disorders such as diabetes. His lab uses pharmacology, biochemistry and molecular biology techniques to pursue its research objectives.
1,*
1
Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, St. John’s, University, Queens, NY 11439, USA
2
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
3
The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
*
Author to whom correspondence should be addressed.
Submission received: 6 June 2024
/
Revised: 9 July 2024
/
Accepted: 19 July 2024
/
Published: 30 July 2024
Simple Summary
Pancreatic ductal adenocarcinoma has a low 5-year survival rate due to delayed diagnosis, rapid growth, tumor complexity, and difficulties in surgical resection. Treatments involving new targeted chemotherapeutic options are required due to challenges such as drug resistance, low efficacy, severe toxicity, high metastatic potential, and clinical trial failures. This study demonstrates the preclinical efficacy and potential of the novel combination of abemaciclib and panobinostat in multiple pancreatic cancer cell lines. Our results depict that a novel combination of these agents aids in synergistic effects, causing cell death in pancreatic cancer cells.
Abstract
The current 5-year survival rate of pancreatic cancer is about 12%, making it one of the deadliest malignancies. The rapid metastasis, acquired drug resistance, and poor patient prognosis necessitate better therapeutic strategies for pancreatic ductal adenocarcinoma (PDAC). Multiple studies show that combining chemotherapeutics for solid tumors has been successful. Targeting two distinct emerging hallmarks, such as non-mutational epigenetic changes by panobinostat (Pan) and delayed cell cycle progression by abemaciclib (Abe), inhibits pancreatic cancer growth. HDAC and CDK4/6 inhibitors are effective but are prone to drug resistance and failure as single agents. Therefore, we hypothesized that combining Abe and Pan could synergistically and lethally affect PDAC survival and proliferation. Multiple cell-based assays, enzymatic activity experiments, and flow cytometry experiments were performed to determine the effects of Abe, Pan, and their combination on PDAC cells and human dermal fibroblasts. Western blotting was used to determine the expression of cell cycle, epigenetic, and apoptosis markers. The Abe-Pan combination exhibited excellent efficacy and produced synergistic effects, altering the expression of cell cycle proteins and epigenetic markers. Pan, alone and in combination with Abe, caused apoptosis in pancreatic cancer cells. Abe-Pan co-treatment showed relative safety in normal human dermal fibroblasts. Our novel combination treatment of Abe and Pan shows synergistic effects on PDAC cells. The combination induces apoptosis, shows relative safety, and merits further investigation due to its therapeutic potential in the treatment of PDAC.
Share and Cite
MDPI and ACS Style
Bhutkar, S.; Yadav, A.; Patel, H.; Barot, S.; Patel, K.; Dukhande, V.V.
Synergistic Efficacy of CDK4/6 Inhibitor Abemaciclib and HDAC Inhibitor Panobinostat in Pancreatic Cancer Cells. Cancers 2024, 16, 2713.
https://doi.org/10.3390/cancers16152713
AMA Style
Bhutkar S, Yadav A, Patel H, Barot S, Patel K, Dukhande VV.
Synergistic Efficacy of CDK4/6 Inhibitor Abemaciclib and HDAC Inhibitor Panobinostat in Pancreatic Cancer Cells. Cancers. 2024; 16(15):2713.
https://doi.org/10.3390/cancers16152713
Chicago/Turabian Style
Bhutkar, Shraddha, Anjali Yadav, Himaxi Patel, Shrikant Barot, Ketan Patel, and Vikas V. Dukhande.
2024. "Synergistic Efficacy of CDK4/6 Inhibitor Abemaciclib and HDAC Inhibitor Panobinostat in Pancreatic Cancer Cells" Cancers 16, no. 15: 2713.
https://doi.org/10.3390/cancers16152713
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