5α-reductase inhibitors are regarded as a promising chemoprevention strategy to reduce the incidence and delay the progression of prostate cancer. Landmark clinical trials have shown the chemopreventive potential of these drugs, but they appear to be mostly effective in mild tumors and have also been correlated with a higher prevalence of advanced prostate cancer. Hence, the use of 5α-reductase inhibitors for prostate cancer chemoprevention has become a controversial issue. The effects of these drugs on prostate cancer growth remain incompletely understood, but they are thought to promote apoptosis in the tumor. Additionally, 5α-reductase inhibitors induce global prostate shrinkage, which decreases the tumor-inhibiting effect of the mechanical stress accumulated in prostatic tissue due to common prostate enlargement with age. Thus, the competition between this mechanical effect and apoptotic upregulation may explain the controversial outcomes of 5α-reductase inhibitors on prostate cancer. Here, we extend our mechanically-coupled model of prostate cancer growth by including the mechanical and apoptotic action of 5α-reductase inhibitors and explore their combined effect on an aggressive tumor in silico. Our simulations show that the apoptotic boost dominates in the first months of therapy but the long-term outcome of 5α-reductase inhibitors depends on its competition with a decrease in hydrostatic stress caused by prostate shrinkage, which favors tumor growth. By combining moderate or strong prostate shrinkage with mild or intense apoptotic upregulation, our simulations show different tumor growth dynamics ranging from long-term inhibition of prostate cancer growth to rapidly growing large tumors, which may evolve towards advanced disease. Thus, our proposed mechanism for the action of 5α-reductase inhibitors may contribute to resolve the controversy around the use of these drugs for chemoprevention and to gain insight on prostate cancer dynamics during its use. The computational technology used herein could also assist physicians to monitor prostatic tumors during 5α-reductase inhibitor therapy and enable the early identification of responders from non-responders in a patient-specific manner.

A numerical simulation study of the dual role of 5α-reductase inhibitors on tumor growth in prostates enlarged by benign prostatic hyperplasia via stress relaxation and apoptosis upregulation

Lorenzo G.;Reali A.;
2020-01-01

Abstract

5α-reductase inhibitors are regarded as a promising chemoprevention strategy to reduce the incidence and delay the progression of prostate cancer. Landmark clinical trials have shown the chemopreventive potential of these drugs, but they appear to be mostly effective in mild tumors and have also been correlated with a higher prevalence of advanced prostate cancer. Hence, the use of 5α-reductase inhibitors for prostate cancer chemoprevention has become a controversial issue. The effects of these drugs on prostate cancer growth remain incompletely understood, but they are thought to promote apoptosis in the tumor. Additionally, 5α-reductase inhibitors induce global prostate shrinkage, which decreases the tumor-inhibiting effect of the mechanical stress accumulated in prostatic tissue due to common prostate enlargement with age. Thus, the competition between this mechanical effect and apoptotic upregulation may explain the controversial outcomes of 5α-reductase inhibitors on prostate cancer. Here, we extend our mechanically-coupled model of prostate cancer growth by including the mechanical and apoptotic action of 5α-reductase inhibitors and explore their combined effect on an aggressive tumor in silico. Our simulations show that the apoptotic boost dominates in the first months of therapy but the long-term outcome of 5α-reductase inhibitors depends on its competition with a decrease in hydrostatic stress caused by prostate shrinkage, which favors tumor growth. By combining moderate or strong prostate shrinkage with mild or intense apoptotic upregulation, our simulations show different tumor growth dynamics ranging from long-term inhibition of prostate cancer growth to rapidly growing large tumors, which may evolve towards advanced disease. Thus, our proposed mechanism for the action of 5α-reductase inhibitors may contribute to resolve the controversy around the use of these drugs for chemoprevention and to gain insight on prostate cancer dynamics during its use. The computational technology used herein could also assist physicians to monitor prostatic tumors during 5α-reductase inhibitor therapy and enable the early identification of responders from non-responders in a patient-specific manner.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11571/1339167
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