A novel combinatorial nanotechnology-based oral chemopreventive regimen demonstrates significant suppression of pancreatic cancer neoplastic lesions.
Pancreatic cancer is a deadly disease killing 37,000 Americans each year. Despite two decades of research on treatment options, the chances of survival are still less than 5% upon diagnosis. Recently, chemopreventive strategies have gained considerable attention as an alternative to treatment. We have previously shown significant in vitro chemopreventive effects with low-dose combinations of aspirin, curcumin, and sulforaphane (ACS) on pancreatic cancer cell lines. Here, we report the results of 24-week chemopreventive study with the oral administration of ACS combinations on the N-nitrosobis (2-oxopropyl) amine (BOP)-treated Syrian golden hamster model to suppress the progression of pancreatic intraepithelial neoplasms (PanIN) using unmodified (free drug) combinations of ACS, and nanoencapsulated (solid lipid nanoparticles; SLN) combinations of aspirin, curcumin, and free sulforaphane. The use of three different doses (low, medium, and high) of unmodified ACS combinations exhibited reduction in tumor incidence by 18%, 50%, and 68.7% respectively; whereas the modified nanoencapsulated ACS regimens reduced tumor incidence by 33%, 67%, and 75%, respectively, at 10 times lower dose compared with the free drug combinations. Similarly, although the unmodified free ACS showed a notable reduction in cell proliferation, the SLN encapsulated ACS regimens showed significant reduction in cell proliferation at 6.3%, 58.6%, and 72.8% as evidenced by proliferating cell nuclear antigen expression. Cell apoptotic indices were also upregulated by 1.5, 2.8, and 3.2 times, respectively, compared with BOP control. These studies provide a proof-of-concept for the use of an oral, low-dose, nanotechnology-based combinatorial regimen for the long-term chemoprevention of pancreatic cancer.
Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, 309 E 2 Street, Pomona, CA 91766, USA.
B Karthik
BK
Grandhi
Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, 309 E 2 Street, Pomona, CA 91766, USA.
Arvind
A
Thakkar
Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, 309 E 2 Street, Pomona, CA 91766, USA.
Jeffrey
J
Wang
Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, 309 E 2 Street, Pomona, CA 91766, USA.
Sunil
S
Prabhu
D000230:Adenocarcinoma / Q000188:drug therapy; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D001241:Aspirin / Q000008:administration & dosage; D002273:Carcinogens / Q000737:chemistry; D045744:Cell Line, Tumor; D006224:Cricetinae; D003474:Curcumin / Q000008:administration & dosage; D004195:Disease Models, Animal; D018450:Disease Progression; D016503:Drug Delivery Systems; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D017879:Isothiocyanates / Q000008:administration & dosage; D008055:Lipids / Q000737:chemistry*; D008297:Male; D008647:Mesocricetus; D053758:Nanoparticles / Q000737:chemistry*; D009602:Nitrosamines / Q000737:chemistry; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D018809:Proliferating Cell Nuclear Antigen / Q000737:chemistry; D013454:Sulfoxides
D000970:Antineoplastic Agents; D002273:Carcinogens; D017879:Isothiocyanates; D008055:Lipids; D009602:Nitrosamines; D018809:Proliferating Cell Nuclear Antigen; D013454:Sulfoxides; C013622:nitrosobis(2-oxopropyl)amine; C016766:sulforaphane; D003474:Curcumin; D001241:Aspirin