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PDA Indolylmaleimides Induce Anti-Tumor Effects in Prostate Carcinoma Cell Lines Through Mitotic Death
Jan Torben Schille1,2, Ingo Nolte2, Julia Beck3
1Department of Medicine, Clinic III-Hematology, Oncology, Palliative Medicine, University of Rostock, Rostock, Germany.
Abstract:
Castrate resistant prostate cancer in men shares several characteristics with canine prostate cancer (PCa). Due to current insufficient therapies, evaluating novel therapeutic agents for late-stage PCa is of considerable interest for both species. PDA indolylmaleimides showed anticancer effects in several neoplastic cell lines. Herein, a comparative characterization of PDA-66 and PDA-377 mediated effects was performed in human and canine PCa cell lines, which is also the first detailed characterization of these agents on cells derived from solid tumors in general. While PDA-377 showed only weak growth inhibition on human PCa cell lines, PDA-66 inhibited proliferation and induced apoptosis in human and canine cell lines with concentrations in the low micromolar range. Morphological characterization and whole transcriptome sequencing revealed that PDA-66 induces mitotic death through its microtubule-depolymerizing ability. PDA-66 appears to be a worthwhile anti-mitotic agent for further evaluation. The similarities in cellular and molecular response observed in the cell lines of both origins form a solid basis for the use of canine PCa in vivo models to gain valuable interchangeable data to the advantage of both species.
Insights
PDA-66, a novel indolylmaleimide, effectively inhibits growth and induces apoptosis in both human and canine prostate cancer cells. This agent targets microtubules, offering a promising therapeutic avenue for advanced prostate cancer in both species.
Area of Science:
- Oncology
- Pharmacology
- Comparative Medicine
Background:
- Castrate-resistant prostate cancer (CRPC) in humans shares similarities with canine prostate cancer (PCa).
- Current therapies for advanced PCa are insufficient, necessitating the evaluation of novel therapeutic agents.
- Indolylmaleimide derivatives, including PDA compounds, have demonstrated anticancer effects in various neoplastic cell lines.
Purpose of the Study:
- To comparatively characterize the effects of PDA-66 and PDA-377 on human and canine prostate cancer cell lines.
- To investigate the mechanism of action of PDA-66 in inducing cell death.
- To establish a basis for using canine PCa models in preclinical studies for human benefit.
Main Methods:
- Comparative cell proliferation and apoptosis assays in human and canine PCa cell lines.
- Morphological characterization of treated cells.
- Whole transcriptome sequencing to elucidate the mechanism of action.
Main Results:
- PDA-66 significantly inhibited proliferation and induced apoptosis in both human and canine PCa cell lines at low micromolar concentrations.
- PDA-377 exhibited only weak growth inhibition in human PCa cell lines.
- PDA-66 was found to induce mitotic death via microtubule depolymerization.
Conclusions:
- PDA-66 is a potent anti-mitotic agent with efficacy in both human and canine prostate cancer models.
- The observed similarities in cellular and molecular responses support the use of canine PCa models for preclinical research benefiting both species.
- PDA-66 warrants further investigation as a potential therapeutic agent for advanced prostate cancer.
Related Concept Videos
02:23Abnormal Proliferation
01:15Drugs that Stabilize Microtubules
02:34Inhibition of Cdk Activity
01:31The Intrinsic Apoptotic Pathway