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NQO1-Responsive Prodrug for in Cellulo Release of Cytochalasin B as Cancer Cell-Targeted Migrastatic
Mervic D Kagho1, Katharina Schmidt2, Christopher Lambert2,3,4
1Department of Chemistry and Molecular Biology, Division of Organic and Medicinal Chemistry, University of Gothenburg, Natrium, Medicinaregatan 7B, Gothenburg, 413 90, Sweden.
Abstract:
Migrastatic drugs targeting cell motility and suppressing invasiveness of solid tumors, have the potential to bring about a paradigm shift in the treatment of solid cancer. Cytochalasin B (CB) is a potent migrastatic compound, but its clinical use is limited by poor selectivity. Here, a NQO1-responsive prodrug, BQTML-CB is developed, synthesized in three steps from cytochalasin B derived from Preussia similis G22. BQTML-CB is selectively activated in NQO1-positive cancer cells, releasing active CB. In vitro, BQTML-CB significantly inhibits proliferation and migration in NQO1-positive U-2OS cells, causing actin disruption and cytokinesis abnormalities, while sparing NQO1-negative B16-F1 cells. The prodrug shows reduced effects on human neutrophils, indicating reduced immunosuppressive activity of BQTML-CB compared to CB. Co-culture studies reveal a beneficial bystander effect, as cleaved CB diffused into adjacent NQO1-deficient cells. These findings support BQTML-CB as a cancer-targeted prodrug with selective antiproliferative and migrastatic properties, highlighting the potential of C7-OH-modified cytochalasans in cancer therapy.
Insights
A novel NQO1-responsive prodrug, BQTML-CB, selectively targets cancer cells, inhibiting proliferation and migration while sparing healthy cells. This migrastatic agent shows promise for solid cancer therapy with reduced side effects.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Migrastatic drugs offer a new approach to solid cancer treatment by targeting cell motility and invasiveness.
- Cytochalasin B (CB) is a potent migrastatic agent, but its clinical application is hindered by poor selectivity.
- Developing targeted delivery systems is crucial to enhance the efficacy and safety of migrastatic compounds.
Purpose of the Study:
- To develop and synthesize a novel NQO1-responsive prodrug of cytochalasin B (BQTML-CB).
- To evaluate the selective activation and anti-cancer effects of BQTML-CB in NQO1-positive versus NQO1-negative cells.
- To assess the safety profile and potential bystander effects of BQTML-CB in a cancer therapy context.
Main Methods:
- Synthesis of BQTML-CB from cytochalasin B derived from Preussia similis G22.
- In vitro assays to assess proliferation, migration, actin disruption, and cytokinesis in NQO1-positive (U-2OS) and NQO1-negative (B16-F1) cell lines.
- Evaluation of BQTML-CB effects on human neutrophils and co-culture studies to determine bystander effects.
Main Results:
- BQTML-CB was successfully synthesized and selectively activated in NQO1-positive cancer cells, releasing active CB.
- In vitro studies demonstrated significant inhibition of proliferation and migration in NQO1-positive cells, with minimal effects on NQO1-negative cells.
- BQTML-CB exhibited reduced immunosuppressive activity compared to CB and showed a beneficial bystander effect in co-culture models.
Conclusions:
- BQTML-CB functions as a targeted cancer prodrug with selective antiproliferative and migrastatic properties.
- The NQO1-responsive activation mechanism enhances drug selectivity, reducing off-target effects.
- C7-OH-modified cytochalasans represent a promising class of compounds for developing novel cancer therapeutics.
