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Design, synthesis, and anti-cancer evaluation of NQO1-responsive prodrug of gemcitabine
Tian-Yu Hu1, Xin Jin1, Ze-Tao Qi1
1Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, 210009, Jiangsu, China.
Abstract:
Enhancing the efficacy of gemcitabine (dFdC), a widely used nucleoside analogue in cancer therapy, through prodrug strategies to address clinical issues such as drug resistance and safety is a highly appealing and promising approach. This study focused on NQO1, a redox enzyme highly expressed in tumor cells, and designed a novel class of NQO1-responsive dFdC prodrugs. Among these prodrugs, prodrug 2 remained stable in plasma and liver/intestinal S9 fractions, releasing dFdC in an NQO1-dependent manner. Prodrug 2 demonstrated significant antitumor activity against both A549 and MCF-7 cell lines, primarily inducing S-phase arrest and apoptosis. It also inhibited tumor cell colony formation and migration. Additionally, prodrug 2 had the potential to overcome dFdC resistance and can efficiently generate dFdC within cells while producing fewer inactive metabolites (dFdU) than dFdC. Furthermore, in an A549 xenograft tumor model in mice, prodrug 2 significantly reduced tumor volume without affecting survival or body weight. Overall, our study demonstrates that an NQO1-responsive prodrug strategy can effectively enhance the antitumor properties of dFdC. The optimized prodrug 2 warrants further development as a preclinical candidate drug.
Insights
This study developed a novel NQO1-responsive gemcitabine (dFdC) prodrug that shows enhanced antitumor activity and overcomes drug resistance. The prodrug effectively targets cancer cells with minimal impact on healthy tissues, showing preclinical promise.
Area of Science:
- Oncology
- Pharmacology
- Medicinal Chemistry
Background:
- Gemcitabine (dFdC) is a cornerstone nucleoside analogue in cancer therapy.
- Clinical use of dFdC is limited by drug resistance and safety concerns.
- Prodrug strategies offer a promising avenue to enhance dFdC efficacy and safety.
Purpose of the Study:
- To design and evaluate novel NQO1-responsive dFdC prodrugs.
- To assess the stability, tumor-targeting capability, and antitumor efficacy of these prodrugs.
- To investigate the potential of these prodrugs to overcome dFdC resistance.
Main Methods:
- Synthesis and characterization of a novel class of NQO1-responsive dFdC prodrugs.
- In vitro evaluation of prodrug stability in plasma and S9 fractions.
- Assessment of NQO1-dependent dFdC release and cytotoxicity in A549 and MCF-7 cell lines.
- In vivo efficacy study using an A549 xenograft tumor model in mice.
Main Results:
- Prodrug 2 demonstrated stability in plasma and S9 fractions, releasing dFdC in an NQO1-dependent manner.
- Prodrug 2 exhibited significant antitumor activity, inducing S-phase arrest and apoptosis, and inhibiting colony formation and migration.
- Prodrug 2 showed potential to overcome dFdC resistance, generating more active dFdC and fewer inactive metabolites (dFdU).
- In vivo studies showed significant tumor volume reduction in the A549 xenograft model without adverse effects on survival or body weight.
Conclusions:
- NQO1-responsive prodrug strategy effectively enhances the antitumor properties of gemcitabine (dFdC).
- Optimized prodrug 2 demonstrates potent preclinical antitumor activity and overcomes gemcitabine resistance.
- Prodrug 2 warrants further development as a potential anticancer therapeutic.
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