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6-[(1,4-Naphthoquinone-2-yl)methyl]thio-Glucose Conjugates, a Novel Targeted Approach for Advanced Prostate Cancer.

Tobias Busenbender1, Dmitry N Pelageev2, Jessica Hauschild1

  • 1Laboratory of Experimental Oncology, Department of Oncology, Hematology and Bone Marrow Transplantation With Section Pneumology, Hubertus Wald Tumorzentrum - University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

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New targeted therapies exploit the Warburg effect for prostate cancer treatment. Compound PeS-9 shows high efficacy by inducing cancer cell death and inhibiting tumor growth, with potential for combination therapies.

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Area of Science:

  • Oncology
  • Biochemistry
  • Pharmacology

Background:

  • The Warburg effect describes increased glucose uptake in cancer cells, offering a therapeutic target.
  • Prostate cancer cells exhibit enhanced glucose metabolism, making them susceptible to targeted interventions.

Purpose of the Study:

  • To design and evaluate novel 1,4-naphthoquinone-glucose derivatives targeting cancer cell glucose uptake.
  • To investigate the efficacy and mechanism of action of compound PeS-9 in prostate cancer.

Main Methods:

  • Synthesis of 1,4-naphthoquinone-glucose derivatives with a thiomethylene linker.
  • Assessment of cytotoxicity, cellular uptake (GLUT-1 mediated), and molecular signaling pathways.
  • In vitro (tumoroids) and in vivo (xenografts) studies to evaluate anticancer activity and safety.

Main Results:

  • Compound PeS-9 demonstrated high efficacy and selectivity, mediated by GLUT-1 uptake.
  • PeS-9 induced androgen receptor degradation, increased reactive oxygen species, and DNA damage.
  • Mitochondrial targeting led to apoptosis, synergistic effects with PARP inhibitors, and suppressed tumor growth in vivo.

Conclusions:

  • PeS-9 is a promising targeted therapy for GLUT-1-overexpressing tumors, particularly prostate cancer.
  • Its mechanism involves apoptosis induction and synergistic potential with PARP inhibitors.
  • PeS-9 exhibits favorable safety profiles and efficacy in preclinical models.