Paradoxical and contradictory effects of imatinib in two cell line models of hormone-refractory prostate cancer

Cardoso, Henrique J.; Vaz, Cátia V.; Correia, Sara; Figueira, Marília I.; Marques, Ricardo; Maia, Cláudio J.; Socorro, Sílvia

doi:10.1002/pros.22976

Cited by 20 publications

(13 citation statements)

References 85 publications

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“…ABL, the main target of imatinib and nilotinib, was found in PCa cell lines (CWR22Rv1, DU145, LNCaP, and PC‐3 cells), as were other targets, including c‐KIT and PDGFR . The anti‐tumor effects of these drugs on PCa cell lines have been investigated . Consistent with our data, imatinib shows antiproliferative effects on DU145, LNCaP, and PC‐3 cells .…”

Section: Discussionsupporting

confidence: 87%

“…NRTKs such as ABL, SRC, and Janus kinase (JAK) have known roles in the biological processes of cell proliferation, migration, invasion, apoptosis, and angiogenesis in PCa . ABL, the main target of imatinib and nilotinib, was found in PCa cell lines (CWR22Rv1, DU145, LNCaP, and PC‐3 cells), as were other targets, including c‐KIT and PDGFR . The anti‐tumor effects of these drugs on PCa cell lines have been investigated .…”

Section: Discussionmentioning

confidence: 99%

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Tyrosine kinase inhibitor therapy prescribed for non‐urologic diseases can modify PSA titers in urology patients

Sasaki¹,

Franco²,

Ohishi³

et al. 2018

The Prostate

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Background: The tyrosine kinase inhibitors (TKI), imatinib and nilotinib, are used to treat chronic myelogenous leukemia (CML). In three CML patients being monitored for urologic diseases, we observed that switching of TKI therapy affected prostate-specific antigen (PSA) titers. Urologists and other medical professionals need to be aware of the potential side-effects of drugs that patients may be receiving for other indications to modify this important prostate diseases indicator. TKIs may affect PSA titers independent of prostate growth or volume. Materials and Methods:We followed PSA levels in urology patients who were also undergoing TKI treatment for CML. We determined the effects of nilotinib and imatinib on proliferation, AR and PSA expression in the LNCaP and 22Rv1 prostate cancer (PCa) cell lines using real-time PCR and Western blotting. Results: Clinically, nilotinib and dasatinib reversibly reduced PSA titers compared to imatinib. At high doses nilotinib and imatinib both demonstrated antiproliferative effects in the PCa cells. At low doses expression of AR and PSA was decreased by both drugs, at mRNA and protein levels. Nilotinib exerted greater effects at lower doses than imatinib. Conclusions: Nilotinib down-regulates serum PSA in patients being treated for nonurological indications, potentially masking a clinical useful marker, we cannot exclude a similar but smaller effect of imatinib. Nilotinib and imatinib both decreased AR and PSA expression in PCa cell lines with the nilotinib effect evident at lower doses. Urologists must appreciate the effects of drugs provided for other diseases on PSA titers and be aware that sudden changes may not reflect underlying prostatic disease. K E Y W O R D S imatinib, nilotinib, tyrosine kinase inhibitor, prostate specific antigen

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Tyrosine kinase inhibitor therapy prescribed for non‐urologic diseases can modify PSA titers in urology patients

Sasaki¹,

Franco²,

Ohishi³

et al. 2018

The Prostate

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“…8), which followed a previous study showing that RGN is overexpressed in radioresistant pancreatic cell lines established by fractionated irradiation [45]. Also, another study showed A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 25 accelerated healing of radiation-induced injury in mice liver concomitant with increased levels of RGN [72].…”

Section: Accepted Manuscriptmentioning

confidence: 79%

“…Caspase-3 activity assay was performed as previously described [25]. Briefly, 25 μg of total protein extracted from testicles were incubated with reaction buffer (25 mM HEPES, 0.1% CHAPS, 10% sucrose and 10 mM DTT, pH 7.5)…”

Section: Caspase-3 Activity Assaymentioning

confidence: 99%

The protective effect of regucalcin against radiation-induced damage in testicular cells

et al. 2016

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“…To determine whether MLN4924 could enhance radiation efficacy, we performed radiosensitization experiments in two hormone-resistant prostate cancer cell lines, DU145 and PC3 [24, 25]. Firstly, we determined the sensitivity of the two prostate cancer cell lines to MLN4924 as a single agent.…”

Section: Resultsmentioning

confidence: 99%

Radiosensitization by the investigational NEDD8-activating enzyme inhibitor MLN4924 (pevonedistat) in hormone-resistant prostate cancer cells

et al. 2016

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Salvage radiotherapy (SRT) is the first-line treatment for prostate cancer patients with biochemical recurrence following radical prostatectomy, and new specific radiosensitizers are in urgent need to enhance SRT effect. MLN4924 (also known as Pevonedistat), a specific inhibitor of NEDD8-activating enzyme, has recently entered phase I/II clinical trials in several malignancies. By inhibiting cullin neddylation, MLN4924 inactivates Cullin-RING ligases (CRL), which have been validated as an attractive radiosensitizing target. In our study, we demonstrate that MLN4924 can be used as a potent radiosensitizer in hormone-resistant prostate cancer cells. We found that MLN4924 inhibited cullin neddylation and sensitized prostate cancer cells to irradiation (IR). Mechanistically, MLN4924 enhanced IR-induced G2 cell-cycle arrest, by inducing accumulation of WEE1/p21/p27, three well-known CRL substrates. Importantly, siRNA knockdown of WEE1/p21/p27 partially abrogated MLN4924-induced G2 cell-cycle arrest, indicating a causal role of WEE1/p21/p27 in MLN4924-induced radiosensitization. Further mechanistic studies revealed that induction of DNA damage and apoptosis also contributed to MLN4924 radiosensitization in hormone-resistant prostate cancer cells. Our findings lay the foundation for future application of MLN4924 as a potential radiosensitizer in hormone refractory prostate cancer (HRPC).

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Paradoxical and contradictory effects of imatinib in two cell line models of hormone-refractory prostate cancer

Cited by 20 publications

References 85 publications

Tyrosine kinase inhibitor therapy prescribed for non‐urologic diseases can modify PSA titers in urology patients

Tyrosine kinase inhibitor therapy prescribed for non‐urologic diseases can modify PSA titers in urology patients

The protective effect of regucalcin against radiation-induced damage in testicular cells

Radiosensitization by the investigational NEDD8-activating enzyme inhibitor MLN4924 (pevonedistat) in hormone-resistant prostate cancer cells

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