Statin derivatives as therapeutic agents for castration-resistant prostate cancer

Ingersoll, Matthew A.; Miller, Dayton T.; Martinez, October; Wakefield, C. Brent; Hsieh, Kuan Chan; Simha, M. Vijaya; Kao, Ching Huei; Chen, Hui Ting; Batra, Surinder K.; Lin, Ming Fong

doi:10.1016/j.canlet.2016.09.008

Cited by 23 publications

(31 citation statements)

References 47 publications

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“…In this context, the majority of data support that statin use is associated with reduced risk of PCa . Statin derivatives showed reduced tumorigenicity in androgen receptor positive and negative PCa cells . Inhibition of ABCG4 levels by simvastatin resulted in the enhanced accumulation of intracellular Dox.…”

Section: Discussionmentioning

confidence: 99%

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Doxorubicin induces prostate cancer drug resistance by upregulation of ABCG4 through GSH depletion and CREB activation: Relevance of statins in chemosensitization

Mallappa

Neeli

Karnewar

et al. 2019

Molecular Carcinogenesis

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Multidrug resistance mediated by ATP‐binding cassette (ABC) transporters remains a major impediment to cancer chemotherapy. In the present study, we documented that doxorubicin (Dox) or cisplatin‐induced prostate cancer (PCa) chemoresistance is predominantly mediated by the induction of ABCG4 in androgen‐independent PCa cells. Treatment of DU‐145 or PC‐3 cells with Dox significantly enhanced the expression of ABCG4 that resulted in the efflux of intracellular Dox. However, incubation of cells with ABCG4 short hairpin RNA resulted in a significant accumulation of Dox and sensitized cells to Dox‐induced cytotoxicity. Interestingly, simvastatin synergistically potentiated Dox‐induced cytotoxicity by inhibiting ABCG4 in DU‐145 and DU‐145 Doxres cells. Mechanistically, ABCG4 expression was regulated redox‐dependently by intracellular glutathione (GSH) levels. Treatment of cells with N‐acetylcysteine or simvastatin restored Dox‐induced depletion of GSH levels that in turn inhibited ABCG4 levels. In addition, a reduction in GSH levels by Dox caused a nuclear factor‐κB dependent enhancement of c‐Myc expression, which led to cAMP‐regulatory element‐binding protein (CREB) activation. Furthermore, chromatin immunoprecipitation experiments revealed that Dox‐induced CREB activation transcriptionally upregulates ABCG4 expression. These results were further confirmed in an in vivo PCa xenograft mice model. Combination of simvastatin and Dox significantly regressed the tumor growth and size with no noticeable Dox‐induced cardiotoxic side effects. Intriguingly, DU‐145 cells with stably depleted ABCG4 levels not only significantly delayed the development of the tumor but also greatly sensitized the tumor to a low dose of Dox that resulted in complete tumor regression. Collectively, this data reinforces a novel function of ABCG4 in Dox‐mediated chemoresistance, and as a potential therapeutic target in drug‐induced PCa chemoresistance.

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Section: Discussionmentioning

confidence: 99%

“…41 Statin derivatives showed reduced tumorigenicity in androgen receptor positive and negative PCa cells. 42 intracellular Dox. In agreement with this, we have earlier shown that statins by augmenting GSH dependent antioxidant mechanisms inhibit breast cancer proliferation.…”

Section: Discussionmentioning

confidence: 99%

Doxorubicin induces prostate cancer drug resistance by upregulation of ABCG4 through GSH depletion and CREB activation: Relevance of statins in chemosensitization

Mallappa

Neeli

Karnewar

et al. 2019

Molecular Carcinogenesis

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“…Cell migration was assessed via Boyden Chamber transwell assay as described previously [31,37]. Cells were plated at a density of 5 × 10 4 cells into the upper chamber of 24-well plate transwell inserts and allowed to migrate for 24 hours.…”

Section: Methodsmentioning

confidence: 99%

“…Cells were harvested via trypsinization and live cell numbers were counted by Trypan Blue dye exclusion assay using a Cellometer Auto T4 Image-based cell counter (Nexcelom, MA, USA) [7,37]. …”

Section: Methodsmentioning

confidence: 99%

“…Changes in cellular ROS levels upon transfection of LNCaP-AI or p66Shc cDNA subclones with p66Shc shRNA or redox-inactive dominant-negative mutant W134F cDNA were determined via DCF-DA dye analysis [32,37]. 24 hours after transfection, cells were harvested and incubated with phenol red-free medium containing 20 μM DCF-DA dye in darkness for 30 minutes.…”

Section: Methodsmentioning

confidence: 99%

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p66Shc regulates migration of castration-resistant prostate cancer cells

Ingersoll

Chou

Lin

et al. 2018

Cellular Signalling

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Metastatic castration-resistant (CR) prostate cancer (PCa) is a lethal disease for which no effective treatment is currently available. p66Shc is an oxidase previously shown to promote androgen-independent cell growth through generation of reactive oxygen species (ROS) and is elevated in clinical PCa and multiple CR PCa cell lines. We hypothesize p66Shc also increases the migratory activity of PCa cells through ROS and investigate the associated mechanism. Using the transwell assay, our study reveals that the level of p66Shc protein correlates with cell migratory ability across several PCa cell lines. Furthermore, we show hydrogen peroxide treatment induces migration of PCa cells that express low levels of p66Shc in a dose-dependent manner, while antioxidants inhibit migration. Conversely, PCa cells that express high levels of endogenous p66Shc or by cDNA transfection possess increased cell migration which is mitigated upon p66Shc shRNA transfection or expression of oxidase-deficient dominant-negative p66Shc W134F mutant. Protein microarray and immunoblot analyses reveal multiple proteins, including ErbB-2, AKT, mTOR, ERK, FOXM1, PYK2 and Rac1, are activated in p66Shc-elevated cells. Their involvement in PCa migration was examined using respective small-molecule inhibitors. The role of Rac1 was further validated using cDNA transfection and, significantly, p66Shc is found to promote lamellipodia formation through Rac1 activation. In summary, the results of our current studies clearly indicate p66Shc also regulates PCa cell migration through ROS-mediated activation of migration-associated proteins, notably Rac1.

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Combination therapy with novel androgen receptor antagonists and statin for castration‐resistant prostate cancer

et al. 2021

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Background: One of the growth mechanisms of castration-resistant prostate cancer (CRPC) is de novo androgen synthesis from intracellular cholesterol, and statins may be able to inhibit this mechanism. In addition, statins have been reported to suppress the expression of androgen receptors (ARs) in prostate cancer cell lines. In this study, we investigated a combination therapy of novel AR antagonists and statin, simvastatin, for CRPC.Methods: LNCaP, 22Rv1, and PC-3 human prostate cancer cell lines were used. We developed androgen-independent LNCaP cells (LNCaP-LA). Microarray analysis was performed, followed by pathway analysis, and mRNA and protein expression was evaluated by quantitative real-time polymerase chain reaction and Western blot analysis, respectively. Cell viability was determined by MTS assay and cell counts. All evaluations were performed on cells treated with simvastatin and with or without AR antagonists (enzalutamide, apalutamide, and darolutamide).Results: The combination of darolutamide and simvastatin most significantly suppressed proliferation in LNCaP-LA and 22Rv1 cells. In a 22Rv1-derived mouse xenograft model, the combination of darolutamide and simvastatin enhanced the inhibition of cell proliferation. In LNCaP-LA cells, the combination of darolutamide and simvastatin led to reduction in the mRNA expression of the androgen-stimulated genes, KLK2 and PSA; however, this reduction in expression did not occur in 22Rv1 cells. The microarray data and pathway analyses showed that the number of differentially expressed genes in the darolutamide and simvastatin-treated 22Rv1 cells was the highest in the pathway termed "role of cell cycle." Consequently, we focused our efforts on the cell cycle regulator polo-like kinase 1 (PLK1), cyclin-dependent kinase 2 (CDK2), and cell cycle division 25C (CDC25C). In 22Rv1 cells, the combination of darolutamide and simvastatin suppressed the mRNA and protein expression of these three genes. In addition, in PC-3 cells (which lack AR expression), the combination of simvastatin and darolutamide enhanced the suppression of cell proliferation and expression of these genes.

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Statin derivatives as therapeutic agents for castration-resistant prostate cancer

Cited by 23 publications

References 47 publications

Doxorubicin induces prostate cancer drug resistance by upregulation of ABCG4 through GSH depletion and CREB activation: Relevance of statins in chemosensitization

Doxorubicin induces prostate cancer drug resistance by upregulation of ABCG4 through GSH depletion and CREB activation: Relevance of statins in chemosensitization

p66Shc regulates migration of castration-resistant prostate cancer cells

Combination therapy with novel androgen receptor antagonists and statin for castration‐resistant prostate cancer

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