Exploring the Role of Enzalutamide in Combination with Radiation Therapy: An<i>In Vitro</i>Study

Triggiani, Luca; Colosini, Antonella; Buglione, Michela; Pasinetti, Nadia; Orizio, Flavia; Bardoscia, Lilia; Borghetti, Paolo; Maddalo, Marta; Spiazzi, L.; Magrini, Stefano Maria; Bresciani, Roberto

doi:10.21873/anticanres.12619

Cited by 9 publications

(8 citation statements)

References 26 publications

(30 reference statements)

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“…Thus, a combination of radiotherapy with ADT to block repair of DSBs leads to enhanced DNA damage and increased cell death [ 8 , 9 , 10 ]. This has led to testing combinations of radiotherapy with newer inhibitors of AR-LBD such as abiraterone, enzalutamide, apalutamide, and a novel AR-degrader, ASC-J9 [ 21 , 22 , 23 , 24 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants

Bañuelos¹,

Ito²,

Obst³

et al. 2020

Cancers

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Blocking androgen receptor (AR) transcriptional activity by androgen deprivation therapy (ADT) improves the response to radiotherapy for intermediate and high risk prostate cancer. Unfortunately, ADT, antiandrogens, and abiraterone increase expression of constitutively active splice variants of AR (AR-Vs) which regulate DNA damage repair leading to resistance to radiotherapy. Here we investigate whether blocking the transcriptional activities of full-length AR and AR-Vs with ralaniten leads to enhanced sensitivity to radiotherapy. Combination therapies using ralaniten with ionizing radiation were evaluated for effects on proliferation, colony formation, cell cycle, DNA damage, and Western blot analyses in human prostate cancer cells that express both full-length AR and AR-Vs. Ralaniten and a potent next-generation analog (EPI-7170) decreased expression of DNA repair genes whereas enzalutamide had no effect. FACS analysis revealed a dose-dependent decrease of BrdU incorporation with increased accumulation of γH2AX with a combination of ionizing radiation with ralaniten. An additive inhibitory effect on proliferation of enzalutamide-resistant cells was achieved with a combination of ralaniten compounds with ionizing radiation. Ralaniten and EPI-7170 sensitized prostate cancer cells that express full-length AR and AR-Vs to radiotherapy whereas enzalutamide had no added benefit.

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Section: Introductionmentioning

confidence: 99%

Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants

Bañuelos¹,

Ito²,

Obst³

et al. 2020

Cancers

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“…Radiotherapy mainly involves treatment with ionizing radiation (IR), which, by direct or indirect actions, leads to the damage of cellular DNA and subsequently results in cell death (6,7). The efficacy of radiotherapy depends on the sensitivity of tumor cells to radiation; tumors can become insensitive to radiation via the radioresistance of tumor cells or the protection of the tumor microenvironment, leading to the repair of damaged cells following IR (7,8). NSCLC cells frequently develop varying degrees of radiation tolerance in the middle and later stages of radiotherapy, reducing its efficacy (9–11).…”

Section: Introductionmentioning

confidence: 99%

Silencing of heat shock protein 27 increases the radiosensitivity of non‑small cell lung carcinoma cells

Xu¹,

Lin²,

Zheng³

et al. 2019

Mol Med Report

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Radiotherapy is a useful treatment for malignant tumors, including lung carcinoma; however, non-small cell lung carcinoma (NSCLC) is frequently insensitive to radiation. It has been reported that heat shock protein 27 (HSPB1) is a radioresistance-associated protein in nasopharyngeal carcinoma. In the present study, the role of HSPB1 in NSCLC cells induced by irradiation was investigated. The viability of cells was determined by a Cell Counting Kit-8 assay. The apoptotic activity, cell cycle distribution and mitochondrial membrane potential (MMP) of cells were evaluated via flow cytometry. Reverse transcription-quantitative polymerase chain reaction and western blot analyses were employed to measure the expression of various genes and proteins. It was observed that knockdown of HSPB1 with small interfering RNA (si-HSPB1) markedly decreased the viability of A549 NSCLC cells and induced cell cycle arrest in the G2/M phase following exposure to 6 Gy irradiation. Furthermore, it was revealed that si-HSPB1 significantly downregulated cyclin B1 and cyclin G1 expression. Additionally, si-HSPB1 promoted apoptosis and depolarized the MMP of cells exposed to 6 Gy irradiation. The expression levels of B-cell lymphoma-2 (Bcl-2), mitochondrial cytochrome c (cyto c ) and pro-caspase-8 were downregulated, whereas those of Bcl-2 associated X protein (Bax), cytosolic cyto c and cleaved-caspase-8 were upregulated. Collectively, silencing of HSPB1 increased the radiosensitivity of NSCLC cells by reducing cell viability, depolarizing the MMP, arresting the cell cycle in the G2/M phase and promoting cell apoptosis. Therefore, HSPB1 may be a novel target for increasing radiosensitivity in the treatment of NSCLC.

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“…Radiotherapy is a common treatment for localized PC as well as palliative treatment for bone metastases. Enzalutamide plus radiation in vitro sensitizes cells to radiation (93). In trial COU-AA-31(NCT00638690), abiraterone acetate with radiation were safely co-administered to patients with a perceived advantage in palliative bone metastasis response.…”

Section: Resistance and Combination Therapy Strategiesmentioning

confidence: 99%

Second-Generation Antiandrogens: From Discovery to Standard of Care in Castration Resistant Prostate Cancer

2019

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Prostate cancer is the most commonly diagnosed cancer affecting men in the United States. The prostate is a hormone-dependent gland in which androgen hormones testosterone and dihydrotestosterone bind to and activate the androgen receptor, initiating nuclear translocation of androgen receptor and a subsequent signaling cascade. Due to the androgen dependency of the prostate, androgen deprivation therapies have emerged as first line treatment for aggressive prostate cancer. Such therapies are effective until the point at which prostate cancer, through a variety of mechanisms including but not limited to generation of ligand-independent androgen receptor splice variants, or intratumoral androgen production, overcome hormone deprivation. These cancers are androgen ablation resistant, clinically termed castration resistant prostate cancer (CRPC) and remain incurable. First-generation antiandrogens established androgen receptor blockade as a therapeutic strategy, but these therapies do not completely block androgen receptor activity. Efficacy and potency have been improved by the development of second-generation antiandrogen therapies, which remain the standard of care for patients with CRPC. Four second-generation anti-androgens are currently approved by the Food and Drug Administration (FDA); abiraterone acetate, enzalutamide, and recently approved apalutamide and darolutamide. This review is intended to provide a thorough overview of FDA approved second-generation antiandrogen discovery, treatment application, strategies for combination therapy to overcome resistance, and an insight for the potential future approaches for therapeutic inhibition of androgen receptor.

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Exploring the Role of Enzalutamide in Combination with Radiation Therapy: AnIn VitroStudy

Abstract: The combination of enzalutamide with ionizing radiation significantly improves radio-sensitivity of hormone-dependent LNCaP cells. Translated in the clinical practice, our results may help to find additional strategies to improve effectiveness of radiotherapy.

Cited by 9 publications

References 26 publications

Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants

Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants

Silencing of heat shock protein 27 increases the radiosensitivity of non‑small cell lung carcinoma cells

Second-Generation Antiandrogens: From Discovery to Standard of Care in Castration Resistant Prostate Cancer

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