ArticleJournal of cancer research and clinical oncology2022
Apalutamide and autophagy inhibition in a xenograft mouse model of human prostate cancer.
Article in Journal of cancer research and clinical oncology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed, 11 citations in OpenAlex.
- Simultaneous Autophagy and Androgen Receptor Inhibition in a Prostate Cancer Xenograft Model.Cancers · 2024Article
- CAPN2 promotes apalutamide resistance in metastatic hormone-sensitive prostate cancer by activating protective autophagy.Journal of translational medicine · 2024Article
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8 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
backgroundApalutamide (APA) is a next-generation androgen receptor antagonist for the treatment of advanced prostate cancer. We have previously shown that upregulation of autophagy is one of the mechanisms by which prostate cancer (PC) cells survive APA anti-tumor treatment in vitro. Therefore, we investigated the characteristics of the autophagic response to APA treatment, alone and in combination with autophagy inhibition, in an in vivo model.
methodsTumor cells were injected into previously castrated nude mice. Four groups of mice bearing LNCaP xenografts were treated with daily intraperitoneal (i.p.) injections of vehicle (control), APA (10 mg/kg), APA (10 mg/kg) + Chl (Chloroquine, 10 mg/kg) or Chl (10 mg/kg). The animals of each treatment group (3/treatment) were kept for the duration of 2 and 3 weeks. At the end of the experiments, the animals were sacrificed and all samples assessed for tumor weight and size, histological analysis, immunoblotting (WES) and immunofluorescence.
resultsThe tumor weight was significantly reduced in mice treated with APA + Chl (203.2 ± 5.0, SEM, P = 0.0066) compared to vehicle control (380.4 ± 37.0). Importantly, the combined treatment showed a higher impact on tumor weight than APA (320.4 ± 45.5) or Chl (337.9 ± 35) alone. The mice treated with the combination of APA + Chl exhibited a reduced expression of ATG5 (autophagy-related five protein), Beclin 1 and LC3 punctuations and an increase in P62 as visualized by immunofluorescence and WES. In addition, Ki-67 nuclear staining was detected in all samples however reduced in APA + Chl (58%) compared to vehicle control (100%). The reduction in Ki-67 protein was associated with an increase in caspase 3 and endothelial CD31 protein expression.
conclusionThese data demonstrate that a treatment with APA + Chl leads to reduced autophagy levels and to tumor suppression compared to the APA monotherapy. Hence, the increased antitumor effect of APA in combination with autophagy inhibitors might provide a new therapeutic approach potentially translatable to patients.
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