Background: Obesity is an important risk factor of Pancreatic Adenocarcinoma (PA) and it is characterized by the accumulation of excessive body fat and a Body Mass Index (BMI) value greater than 30. Obesity is also characterized by high levels of leptin, which has been consistently associated with the development of many different cancer including pancreatic cancer. Obesity can also alter the epigenome via epigenetics changes as DNA methylation and histones acetylation. Histone lysine residues can be acetylated by Histone Acetyltransferases or deacetylated by Histone Deacetylases (HDAC). Leptin can induce the proliferation of Pancreatic Cancer Stem Cells (PCSC), which are responsible for chemoresistance, invasiveness and reoccurrence of PA. PCSC express specific cell markers and can form tumorspheres in vitro. Our lab developed a leptin antagonist named LPrA2, which was bound to iron oxide nanoparticle (IONP-LPrA2) in order to increase its effectiveness and bioavailability.
Methods: The adjuvant effects of IONP-LPrA2 in combination of chemotherapeutic drugs on PCSC and tumorspheres formation in low attachment plates were determined. Additionally, the effects of IONP-LPrA2 in combination with chemotherapeutic drugs on the differential expression of epigenetic markers HDAC-1, HDAC-2, and HDAC-8 were investigated. The PA cells were cultured in vitro and treated with leptin, IONP-LPrA2, and chemotherapeutics. Then, the expression of epigenetic and PCSC markers, cell proliferation and survival were determined via Nexcelom cellometer or Guava EasyCyte flow cytometer analyses. Results were assessed by western blot analysis.
Results: Leptin affects the level of some HDACs and PCSC markers. That was abrogated by IONP-LPrA2. Chemotherapeutics showed differential effects on the epigenetic and PCSC markers and on tumorspheres formation by PA cells.
Conclusion: These findings suggest that IONP-LPrA2 could be useful to design new PA therapies in combination with chemotherapeutics. Furthermore, IONP-LPrA2 may increase the efficiency of chemotherapeutic drug Gemcitabine. These results could be most relevant for obese patients that show the highest incidence of PA and lowest survival rate.
Citation Format: Cynthia Ines Mantho Tchio, Adriana Harbuzariu, Tia L. Harmon, Derreck J. Beech, Ruben R. Gonzalez-Perez. A new approach to targeted therapy for obesity-related pancreatic adenocarcinoma. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr B31.
- ©2016 American Association for Cancer Research.