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In vitro investigations of troxacitabine (TROX) and 3'-deazanepanocin (DZNep) combination for pancreatic cancer therapy.

J. Manu,Uma S. Singh,E. Agboluaje,Matthew K. Whittaker,Eileen J. Kennedy,Chung K Chu,May P. Xiong

Published 2026 in Bioorganic & Medicinal Chemistry Letters

ABSTRACT

Gemcitabine (GEM) is a first line drug to treat pancreatic cancer (PC). However, its long-term efficacy and potency is plagued with reported chemoresistance. To circumvent this issue, the novel GEM analog called troxacitabine (TROX) was evaluated alone and in combination with the epigenetic drug 3'-deazaneplanocin (DZNep) against PANC-1 cancer cells. Herein, we report on the synergistic interplay between these two nucleoside analogs in combination (i.e. unprimed combinations) and investigate further the effect of priming PANC-1 cells with DZNep at 8 h versus 24 h followed by TROX (i.e. primed combination). Specific doses at 8 h primed combinations displayed the greatest degree of synergy and were observed between 1.25 and 5 μM DZNep and 0.5-2 μM TROX in the HSA model, and 1.25-5 μM DZNep and 0.12-0.5 μM TROX in the Loewe model. Data revealed that 8 h primed combinations of DZNep/TROX also reduced self-renewal capability, migratory, and invasive properties of PANC-1 cells more effectively than unprimed (simultaneous) combinations. Proper timed combination of DZNep and TROX may pave the path for an alternative treatment option for GEM-resistant PC.

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