Overcoming Chemotherapy Resistance in Prostate Cancer

Madan, Ravi A.; Pal, Sumanta K.; Sartor, Oliver; Dahut, William L.

doi:10.1158/1078-0432.ccr-10-2654

Cited by 62 publications

(47 citation statements)

References 60 publications

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“…Many tumor types are refractory and/or develop acquired resistance to these drugs (5-7). Paclitaxel and docetaxel both have a high affinity for multidrug resistance proteins (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative Mechanism of Action of the Novel Taxane Cabazitaxel as Compared with the Parent Compound Docetaxel in MCF7 Breast Cancer Cells

Azarenko

Smiyun

Mah

et al. 2014

Molecular Cancer Therapeutics

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Cabazitaxel, a novel chemotherapeutic taxane, is effective against docetaxel-resistant cells and tumors. It is approved for treatment of metastatic hormone-refractory prostate cancer in patients pretreated with docetaxel. Objective responses have been observed in many other cancers, including pretreated metastatic breast cancer. Cabazitaxel and docetaxel share a high degree of structural similarity. The basis for cabazitaxel's efficacy is unclear, and its mechanism has not been described. We compared the effects of cabazitaxel and docetaxel on MCF7 human breast cancer cells expressing fluorescent tubulin. Both drugs inhibited cell proliferation (IC 50s , cabazitaxel, 0.4 AE 0.1 nmol/L, docetaxel, 2.5 AE 0.5 nmol/L) and arrested cells in metaphase by inducing mitotic spindle abnormalities. Drug concentrations required for halfmaximal mitotic arrest at 24 hours were similar (1.9 nmol/L cabazitaxel and 2.2 nmol/L docetaxel). Cabazitaxel suppressed microtubule dynamic instability significantly more potently than docetaxel. In particular, cabazitaxel (2 nmol/L) suppressed the microtubule shortening rate by 59% (compared with 49% for 2 nmol/L docetaxel), the growing rate by 33% (vs. 19%), and overall dynamicity by 83% (vs. 64%). Cabazitaxel was taken up into cells significantly faster than docetaxel, attaining an intracellular concentration of 25 mmol/L within 1 hour, compared with 10 hours for docetaxel. Importantly, after washing, the intracellular cabazitaxel concentration remained high, whereas the docetaxel concentration was significantly reduced. The data indicate that the potency of cabazitaxel in docetaxel-resistant tumors is due to stronger suppression of microtubule dynamics, faster drug uptake, and better intracellular retention than occurs with docetaxel.

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“…Many tumor types are refractory and/or develop acquired resistance to these drugs (5-7). Paclitaxel and docetaxel both have a high affinity for multidrug resistance proteins (7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative Mechanism of Action of the Novel Taxane Cabazitaxel as Compared with the Parent Compound Docetaxel in MCF7 Breast Cancer Cells

Azarenko

Smiyun

Mah

et al. 2014

Molecular Cancer Therapeutics

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“…5,6 A maximum of 12 cycles was given in the SWOG trial, and the treatment duration in all three arms of the TAX327 trial was 10 cycles, a length of time that was arbitrarily selected. The optimal duration of this regimen has not been established; 7,8 however, standard DTX chemotherapy is typically administered without pauses until unacceptable toxicity or disease progression. Thus, responding patients are exposed to uninterrupted chemotherapy for prolonged periods, with a consequent increased risk of toxicity.…”

Section: Introductionmentioning

confidence: 99%

Intermittent tri-weekly docetaxel plus bicalutamide in patients with castration-resistant prostate cancer: a single-arm prospective study using a historical control for comparison

Zhang²,

Tao-tao³

et al. 2013

Asian J Androl

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Whether continuous docetaxel (DTX) chemotherapy offers an advantage over intermittent therapy for castration-resistant prostate cancer (CRPC) is unknown. In this study, we evaluated the efficacy, toxicity and quality of life (QoL) of intermittent tri-weekly DTX with bicalutamide in CRPC. Forty-two patients (group A) with CRPC were enrolled. The patients received intravenous DTX (75 mg m 22 ) once tri-weekly with oral bicalutamide (50 mg) once daily. Patients had a DTX holiday when the prostate-specific antigen (PSA) level declined o50%. DTX was restarted in patients with a PSA increase o25%. Sixty patients (group B) who had matching characteristics and had continuously received DTX without bicalutamide for 10-12 cycles were also enrolled. There were no statistically significant differences in progression-free survival (8 months vs. 9 months, P50.866) or overall survival (19 months vs. 21 months, P50.753) between groups A and B; however, the proportions of patients in group A with all grades of neutropenia (33% vs. 58%, P50.013) and nausea/vomiting (11% vs. 29%, P50.024) were significantly less compared to group B. A significant improvement in the global health and fatigue scores was recorded for group A post-chemotherapy compared to pre-chemotherapy (P,0.05). The fatigue, nausea/ vomiting and appetite loss scores in group B were increased post-chemotherapy compared to pre-chemotherapy (P,0.05). In conclusion, intermittent tri-weekly DTX plus bicalutamide is well tolerated and has the potential to achieve comparable disease control with an improvement in QoL for patients with CRPC.

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“…DTX can impair microtubule function and lead to decreased AR nuclear translocation (31). However, AR nuclear translocation is significantly enhanced following long-term DTX chemotherapy or the occurrence of resistance to DTX in prostate cancer (3,32). Therefore, DTX-induced AR signaling changes may be treated with anti-androgen therapy, and DTX combined with anti-androgen therapy may have a synergistic effect.…”

Section: Discussionmentioning

confidence: 99%

“…Docetaxel (DTX) induces apoptotic cell death by stabilizing β-tubulin, thereby blocking mitotic cell division and inhibiting androgen receptor nuclear translocation (2). DTX is the standard first-line drug for the treatment of CRPC, however, only ~48% of patients respond to DTX, and acquired drug resistance rapidly develops in DXT chemotherapy (3). Patients with DTX-resistant or -progressive CRPC previously treated with DTX, cabazitaxel (4), abiraterone acetate (5) enzalutamide (6), sipuleucel-T (7) and radium 223-dichloride (8) have shown an improvement in overall survival time over the placebo group in phase III clinical trials.…”

Section: Introductionmentioning

confidence: 99%

“…Finally, the high activity of drug-detoxifying proteins, including glutathione-S-transferase and cytochrome P450 3A, increases DTX metabolism (16,17). Accordingly, several inhibitors that target these mechanisms have been developed; however, clinical trials of these agents as single or combination therapies have exhibited only limited clinical efficacy (3,18). Thus, the identification of new molecular mechanisms of DTX resistance and the development of novel targeted treatment strategies are urgently required for CRPC.…”

Section: Introductionmentioning

confidence: 99%

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Targeting MRP4 expression by anti-androgen treatment reverses MRP4-mediated docetaxel resistance in castration-resistant prostate cancer

Zhang

et al. 2017

Oncology Letters

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Abstract. It has been demonstrated that docetaxel (DTX) may improve the overall survival of patients with castration-resistant prostate cancer (CRPC). However, its effectiveness is limited with time, and tumor escape is eventually inevitable. DTX resistance is the main reason for the failure of chemotherapy for CRPC. In the present study, the expression status of multidrug resistance protein 4 (MRP4) in DTX-resistant prostate cancer cells was investigated, and it was explored whether anti-androgen treatment may inhibit MRP4 expression and overcome DTX resistance. DTX-resistant C4-2/D cells were established by exposing DTX-sensitive C4-2/S cells to gradually increasing concentrations of DTX. MRP4 gene expression and the effect of androgen signaling on its expression were assessed by reverse transcription-polymerase chain reaction and western blotting. Intracellular and extracellular concentrations of DTX were detected by high-performance liquid chromatography. Anti-androgen treatment effects on DTX sensitivity were determined by a clonogenic test and an MTT cytotoxicity assay. MRP4 was overexpressed in C4-2/D cells, while its expression was barely detectable in C4-2/S cells. MRP4 expression levels were elevated in C4-2/D cells by dihydrotestosterone, whereas they were blocked by anti-androgen bicalutamide (BKL) treatment. Intracellular and extracellular DTX concentrations in C4-2/D cells were associated with MRP4 levels. The downregulation of MRP4 by BKL increased the intracellular concentration of DTX in C4-2/D cells and re-sensitized C4-2/D cells to DTX. These results indicated that overexpression of MRP4 mediates acquired DTX resistance, and suggest that targeting MRP4 expression by anti-androgen treatment may reverse DTX-resistant prostate cancer cells to DTX chemotherapy.

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Overcoming Chemotherapy Resistance in Prostate Cancer

Cited by 62 publications

References 60 publications

Antiproliferative Mechanism of Action of the Novel Taxane Cabazitaxel as Compared with the Parent Compound Docetaxel in MCF7 Breast Cancer Cells

Antiproliferative Mechanism of Action of the Novel Taxane Cabazitaxel as Compared with the Parent Compound Docetaxel in MCF7 Breast Cancer Cells

Intermittent tri-weekly docetaxel plus bicalutamide in patients with castration-resistant prostate cancer: a single-arm prospective study using a historical control for comparison

Targeting MRP4 expression by anti-androgen treatment reverses MRP4-mediated docetaxel resistance in castration-resistant prostate cancer

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