Abstract
Human castration-resistant prostate cancer (CRPC) is a significant target of clinical research. The use of DNA-damaging agents has a long history in cancer chemotherapy but is limited by their toxicities. The combination with a safer drug can be a strategy in reducing dosage and toxicity while increasing anticancer activity in CRPC treatment. Phosphodiesterase type 5 (PDE5) inhibitors are used to treat erectile dysfunction through the selective inhibition of PDE5 that is responsible for cGMP degradation in the corpus cavernosum. Several studies have reported that PDE5 inhibitors display protective effect against doxorubicin-induced cardiotoxicity. The combinatory treatment of CRPC with doxorubicin and PDE5 inhibitors has been studied accordingly. The data demonstrated that sildenafil or vardenafil (two structure-related PDE5 inhibitors) but not tadalafil (structure-unrelated to sildenafil) sensitized doxorubicin-induced apoptosis in CRPC cells with deteriorating the down-regulation of anti-apoptotic Bcl-2 family members, including Bcl-xL and Mcl-1, and amplifying caspase activation. Homologous recombination (HR) and non-homologous end joining (NHEJ) DNA repair systems were inhibited in the apoptotic sensitization through detection of nuclear foci formation of Rad51 and DNA end-binding of Ku80. PDE5 knockdown to mimic the exposure to PDE5 inhibitors did not reproduce apoptotic sensitization, suggesting a PDE5-independent mechanism. Not only doxorubicin, sildenafil combined with other inhibitors of topoisomerase II but not topoisomerase I also triggered apoptotic sensitization. In conclusion, the data suggest that sildenafil and vardenafil induce PDE5-independent apoptotic sensitization to doxorubicin (or other topoisomerase II inhibitors) through impairment of both HR and NHEJ repair systems that are evident by a decrease of nuclear Rad51 levels and their foci formation in the nucleus, and an inhibition of Ku80 DNA end-binding capability. The combinatory treatment may enable an important strategy for anti-CRPC development.
Highlights
DNA-damaging agents have a long history of use in cancer chemotherapy
The data demonstrated that doxorubicin, by itself, induced a significant decrease of cell population at G0/G1 phase associated with an increase at both S and G2/M phases
The data suggest that sildenafil and vardenafil, at least partly, induce a Phosphodiesterase type 5 (PDE5)-independent apoptotic sensitization in the presence of doxorubicin in castration-resistant prostate cancer (CRPC) cells in a sequential manner (Figure 7)
Summary
DNA-damaging agents have a long history of use in cancer chemotherapy. Use of these agents is limited by dose-limiting toxicities and development of drug resistance [1, 2]. Doxorubicin interacts with DNA through intercalation and inhibition of macromolecular biosynthesis and inhibition of topoisomerase II, leading to DNA double strand breaks (DSB) of the cells [6]. The resistance can occur when DNA damage-sensing and repair capacities alter in response to the stresses [7]. DSB can be repaired through two major mechanisms: homologous recombination (HR) and non-homologous end joining (NHEJ). NHEJ is the major DSB rejoining process and occurs in all cell cycle phases [8]. Since DNA repair is a crucial chemoresistance mechanism, the combination treatments with agents that act through different mechanisms of action may hinder DNA repair capability and improve chemosensitizing effect
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