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Updated: Jun 18, 2025
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Overcoming ABCB1 mediated multidrug resistance in castration resistant prostate cancer
Sadia Sarwar1, Viacheslav M Morozov1, Mallory A Newcomb1
1Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, FL, USA.
Abstract:
Prostate cancer (PCa) is the second leading cause of cancer-related death in American men. PCa that relapses after hormonal therapies, referred to as castration resistant PCa (CRPC), often presents with metastases (mCRPC) that are the major cause of mortality. The few available therapies for mCRPC patients include taxanes docetaxel (DTX) and cabazitaxel (CBZ). However, development of resistance limits their clinical use. Mechanistically, resistance arises through upregulation of multidrug resistance (MDR) proteins such as MDR1/ABCB1, making ABCB1 an attractive therapeutic target. Yet, ABCB1 inhibitors failed to be clinically useful due to low specificity and toxicity issues. To study taxanes resistance, we produced CBZ resistant C4-2B cells (RC4-2B) and documented resistance to both CBZ and DTX in cell culture and in 3D prostaspheres settings. RNAseq identified increased expression of ABCB1 in RC4-2B, that was confirmed by immunoblotting and immunofluorescent analysis. ABCB1-specific inhibitor elacridar reversed CBZ and DTX resistance in RC4-2B cells, confirming ABCB1-mediated resistance mechanism. In a cell-based screen using a curated library of cytotoxic drugs, we found that DNA damaging compounds Camptothecin (CPT) and Cytarabine (Ara-C) overcame resistance as seen by similar cytotoxicity in parental C4-2B and resistant RC4-2B. Further, these compounds were cytotoxic to multiple PC cells resistant to taxanes with high ABCB1 expression and, therefore, can be used to conquer the acquired resistance to taxanes in PCa. Finally, inhibition of cyclin-dependent kinases 4/6 (CDK4/6) with small molecule inhibitors (CDK4/6i) potentiated cytotoxic effect of CPT or Ara-C in both parental and resistant cells. Overall, our findings indicate that DNA damaging agents CPT and Ara-C alone or in combination with CDK4/6i can be suggested as a new treatment regimen in CRPC patients, including those that are resistant to taxanes.
Insights
New DNA damaging drugs, Camptothecin (CPT) and Cytarabine (Ara-C), overcome taxane resistance in prostate cancer (PCa). Combining these agents with CDK4/6 inhibitors offers a promising new treatment for castration-resistant PCa (CRPC).
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Prostate cancer (PCa) relapse after hormonal therapy leads to castration-resistant PCa (CRPC), often with metastases (mCRPC).
- Taxanes (docetaxel, cabazitaxel) are key therapies for mCRPC, but resistance limits their efficacy.
- Multidrug resistance (MDR) protein ABCB1 (MDR1) upregulation is a primary mechanism of taxane resistance, but existing inhibitors have toxicity issues.
Purpose of the Study:
- To investigate novel therapeutic strategies to overcome taxane resistance in CRPC.
- To identify agents that can restore sensitivity to taxanes or exhibit efficacy in resistant cells.
- To evaluate the potential of combining DNA damaging agents with CDK4/6 inhibitors.
Main Methods:
- Generated cabazitaxel-resistant C4-2B cells (RC4-2B) to model CRPC taxane resistance.
- Confirmed increased ABCB1 expression in resistant cells using RNAseq, immunoblotting, and immunofluorescence.
- Screened a library of cytotoxic drugs and tested DNA damaging agents (Camptothecin, Cytarabine) for efficacy against resistant cells.
- Assessed the effect of CDK4/6 inhibitors (CDK4/6i) in combination with Camptothecin or Cytarabine.
Main Results:
- Resistant RC4-2B cells showed cross-resistance to docetaxel and cabazitaxel, mediated by increased ABCB1 expression.
- DNA damaging agents Camptothecin (CPT) and Cytarabine (Ara-C) demonstrated potent cytotoxicity in both parental and taxane-resistant PCa cells.
- CPT and Ara-C were effective against multiple PCa cell lines with high ABCB1 expression, indicating broad applicability.
- Inhibition of CDK4/6 potentiated the cytotoxic effects of CPT and Ara-C in both sensitive and resistant cells.
Conclusions:
- Camptothecin and Cytarabine are effective in overcoming acquired taxane resistance in prostate cancer, potentially through targeting ABCB1-mediated resistance.
- Combination therapy with DNA damaging agents and CDK4/6 inhibitors presents a novel and promising treatment approach for castration-resistant prostate cancer patients, including those with taxane resistance.
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