Pharmacological reversal of histone methylation presensitizes pancreatic cancer cells to nucleoside drugs: in vitro optimization and novel nanoparticle delivery studies.
We evaluated the potential of an investigational histone methylation reversal agent, 3-deazaneplanocin A (DZNep), in improving the chemosensitivity of pancreatic cancer to nucleoside analogs (i.e., gemcitabine). DZNep brought delayed but selective cytotoxicity to pancreatic cancer cells without affecting normal human pancreatic ductal epithelial (HPDE) cells. Co-exposure of DZNep and gemcitabine induced cytotoxic additivity or synergism in both well- and poorly-differentiated pancreatic cell lines by increased apoptosis. In contrast, DZNep exerted antagonism with gemcitabine against HPDE cells with significant reduction in cytotoxicity compared with the gemcitabine-alone regimen. DZNep marginally depended on purine nucleoside transporters for its cytotoxicity, but the transport dependence was circumvented by acyl derivatization. Drug exposure studies revealed that a short priming with DZNep followed by gemcitabine treatment rather than co-treatment of both agents to produce a maximal chemosensitization response in both gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cells. DZNep rapidly and reversibly decreased trimethylation of histone H3 lysine 27 but increased trimethylation of lysine 9 in an EZH2- and JMJD1A/2C-dependent manner, respectively. However, DZNep potentiation of nucleoside analog chemosensitization was found to be temporally coupled to trimethylation changes in lysine 27 and not lysine 9. Polymeric nanoparticles engineered to chronologically release DZNep followed by gemcitabine produced pronounced chemosensitization and dose-lowering effects. Together, our results identify that an optimized DZNep exposure can presensitize pancreatic cancer cells to anticancer nucleoside analogs through the reversal of histone methylation, emphasizing the promising clinical utilities of epigenetic reversal agents in future pancreatic cancer combination therapies.
Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia, United States of America.
Sau Wai
SW
Hung
Hardik
H
Mody
Sean
S
Marrache
Yangzom D
YD
Bhutia
Franklin
F
Davis
Jong Hyun
JH
Cho
Jason
J
Zastre
Shanta
S
Dhar
Chung K
CK
Chu
Rajgopal
R
Govindarajan
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects; D003692:Delayed-Action Preparations; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors; D006801:Humans; D053758:Nanoparticles; D009705:Nucleosides / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014981:Xenopus; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D003692:Delayed-Action Preparations; D009705:Nucleosides; D003841:Deoxycytidine; C048460:3-deazaneplanocin; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D000241:Adenosine; D000093542:Gemcitabine