title: Zyflamend suppresses growth and sensitizes human pancreatic tumors to gemcitabine in an orthotopic mouse model through modulation of multiple targets.
abstract: Agents that can potentiate the efficacy of standard chemotherapy against pancreatic cancer are of great interest. Because of their low cost and safety, patients commonly use a variety of dietary supplements, although evidence of their efficacy is often lacking. One such commonly used food supplement is Zyflamend, a polyherbal preparation with potent anti-inflammatory activities and preclinical efficacy against prostate and oral cancer. Whether Zyflamend has any efficacy against human pancreatic cancer alone or in combination with gemcitibine, a commonly used agent, was examined in cell cultures and in an orthotopic mouse model. In vitro, Zyflamend inhibited the proliferation of pancreatic cancer cell lines regardless of p53 status and also enhanced gemcitabine-induced apoptosis. This finding correlated with inhibition of NF-κB activation by Zyflamend and suppression of cyclin D1, c-myc, COX-2, Bcl-2, IAP, survivin, VEGF, ICAM-1 and CXCR4. In nude mice, oral administration of Zyflamend alone significantly inhibited the growth of orthotopically transplanted human pancreatic tumors, and when combined with gemcitabine, further enhanced the antitumor effects. Immunohistochemical and Western blot analyses of tumor tissue showed that the suppression of pancreatic cancer growth correlated with inhibition of proliferation index marker (Ki-67), COX-2, MMP-9, NF-κB and VEGF. Overall, these results suggest that the concentrated multiherb product Zyflamend alone can inhibit the growth of human pancreatic tumors and, in addition, can sensitize pancreatic cancers to gemcitabine through the suppression of multiple targets linked to tumorigenesis.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ajaikumar B
authors.initials: AB
authors.lastname: Kunnumakkara
authors.forename: Bokyung
authors.initials: B
authors.lastname: Sung
authors.forename: Jayaraj
authors.initials: J
authors.lastname: Ravindran
authors.forename: Parmeswaran
authors.initials: P
authors.lastname: Diagaradjane
authors.forename: Amit
authors.initials: A
authors.lastname: Deorukhkar
authors.forename: Sanjit
authors.initials: S
authors.lastname: Dey
authors.forename: Cemile
authors.initials: C
authors.lastname: Koca
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Tong
authors.forename: Juri G
authors.initials: JG
authors.lastname: Gelovani
authors.forename: Sushovan
authors.initials: S
authors.lastname: Guha
authors.forename: Sunil
authors.initials: S
authors.lastname: Krishnan
authors.forename: Bharat B
authors.initials: BB
authors.lastname: Aggarwal
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010936:Plant Extracts / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D019394:Ki-67 Antigen; D016328:NF-kappa B; D010936:Plant Extracts; D016159:Tumor Suppressor Protein p53; C519312:Zyflamend; D003841:Deoxycytidine; D000093542:Gemcitabine