Dietary Garcinol Arrests Pancreatic Cancer in p53 and K-ras Conditional Mutant Mouse Model

Abstract

Pancreatic cancer (PC) patients have poor prognosis and survival rate. Gemcitabine, the drug of choice has a dismal 15% response rate. Earlier, we reported that Garcinol alone and in combination with gemcitabine showed a dose-dependent favorable response on PC cell lines. This study probes the in vivo effects of dietary Garcinol on PC progression in transgenic PC mice (KPC; K-ras and p53 conditional mutant). KPC male mice were divided into: KC- Control diet; KGr-0.05% Garcinol diet; KGm-Gemcitabine injected; KGG – Garcinol diet + Gemcitabine injected groups. Changes in tumor progression, toxicity, or cell morphology were monitored by magnetic resonance imaging, Fore-stomach, and blood smear, respectively. Pancreatic Intraepithelial Neoplasia (mPanIN) grading with hematoxylin and eosin (H&E) staining was conducted on pancreas and validated by immunohistochemistry. The KGr group showed improved survival, no observable toxicity with marked reduction in papilloma formation in the fore-stomach, and a higher ratio of NK and NKT cells compared to Non-NK lymphocytes. Additionally, the KGr, KGm, and KGG groups showed reduction in tumor volumes and reduced number of advanced mouse PanIN3. Dietary Garcinol alone and in combination with gemcitabine retarded the progression of PC in transgenic PC mice, arresting the cancer in the earlier stages, improving prognosis and survival.

Keywords:

• Pancreatic cancer
• garcinol
• PKC transgenic mice
• histology

Acknowledgments

Bryn Eagleson, Tristan Kempston, Brittany Merrifield, Van Andel Institute for the mouse model. Dr. Ewart M. Haacke, HUH-MR Research Facility, Wayne State University for his expertise with the MRI.

Disclosure Statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Wayne State University Intramural Funds to Smiti Gupta and Malaysian Oil Palm Board for funds for this research work.

Notes on contributors

Nadia Saadat

NS: Responsible for the overall animal study, draft manuscript preparation. SA: Prepared and read the histology slides under the supervision of Dr. David. NHR, AG, AGoja: Animal care, procedures, plasma and tissue collection. YS: conducted the MRI scans. DD: Trained students on pancreatic histopathology, confirmed histological data, and SVG: Overall design and implementation of the study, manuscript writing.

Sarah Akhtar

NS: Responsible for the overall animal study, draft manuscript preparation. SA: Prepared and read the histology slides under the supervision of Dr. David. NHR, AG, AGoja: Animal care, procedures, plasma and tissue collection. YS: conducted the MRI scans. DD: Trained students on pancreatic histopathology, confirmed histological data, and SVG: Overall design and implementation of the study, manuscript writing.

Arvind Goja

NS: Responsible for the overall animal study, draft manuscript preparation. SA: Prepared and read the histology slides under the supervision of Dr. David. NHR, AG, AGoja: Animal care, procedures, plasma and tissue collection. YS: conducted the MRI scans. DD: Trained students on pancreatic histopathology, confirmed histological data, and SVG: Overall design and implementation of the study, manuscript writing.

Nurul H. Razalli

NS: Responsible for the overall animal study, draft manuscript preparation. SA: Prepared and read the histology slides under the supervision of Dr. David. NHR, AG, AGoja: Animal care, procedures, plasma and tissue collection. YS: conducted the MRI scans. DD: Trained students on pancreatic histopathology, confirmed histological data, and SVG: Overall design and implementation of the study, manuscript writing.

Andreea Geamanu

NS: Responsible for the overall animal study, draft manuscript preparation. SA: Prepared and read the histology slides under the supervision of Dr. David. NHR, AG, AGoja: Animal care, procedures, plasma and tissue collection. YS: conducted the MRI scans. DD: Trained students on pancreatic histopathology, confirmed histological data, and SVG: Overall design and implementation of the study, manuscript writing.

Doina David

NS: Responsible for the overall animal study, draft manuscript preparation. SA: Prepared and read the histology slides under the supervision of Dr. David. NHR, AG, AGoja: Animal care, procedures, plasma and tissue collection. YS: conducted the MRI scans. DD: Trained students on pancreatic histopathology, confirmed histological data, and SVG: Overall design and implementation of the study, manuscript writing.

Yimin Shen

NS: Responsible for the overall animal study, draft manuscript preparation. SA: Prepared and read the histology slides under the supervision of Dr. David. NHR, AG, AGoja: Animal care, procedures, plasma and tissue collection. YS: conducted the MRI scans. DD: Trained students on pancreatic histopathology, confirmed histological data, and SVG: Overall design and implementation of the study, manuscript writing.

Smiti Vaid Gupta

NS: Responsible for the overall animal study, draft manuscript preparation. SA: Prepared and read the histology slides under the supervision of Dr. David. NHR, AG, AGoja: Animal care, procedures, plasma and tissue collection. YS: conducted the MRI scans. DD: Trained students on pancreatic histopathology, confirmed histological data, and SVG: Overall design and implementation of the study, manuscript writing.