Despite recent therapeutic approaches that have significantly increased survival, most prostate aggressive tumors become resistant to current treatment protocols [8, 121]. Prostate cancers that initially respond to standard chemotherapy often recur with selective outgrowth of tumor cell subpopulations that are resistant not only to the original chemotherapeutic agents, but also to other therapeutics . Several events are thought to be involved in the dysregulation of pathways, which may activate a different pathway(s) for androgen independence probably through a paracrine androgen-independent pathway, which may explain the multifocality and heterogeneity of prostate cancer and for hormone therapy resistance. Indeed, in a xenograft model, most of androgen-responsive genes that were initially downregulated under conditions of androgen deprivation were later re-expressed in recurrence tumors, indicating failure of androgen-derivation therapy as well as irreversible commitment to tumor progression .
The array of genes that comprise the proliferation status may differ in different type of tumors. Evidence has demonstrated that the cell cycle regulation is frequently altered in prostate cancers, in part, by the interplay of oncogenic cascades activation with diverse hormones, growth factors, and cytokines. Moreover, the accumulation of mutations in prostate cancer cells may eventually lead to a more poorly differentiated and aggressive tumor behavior, leading to overall higher rates of progression and worse prognosis, irrespective of the size of the lesion [124-127]. Multiple cellular signaling pathways including, protein kinase B (Akt), mitogen-activated protein kinase (MAPK), the nuclear factor kappa B (NF-kB), transforming growth factor beta (TGF-p), the vascular endothelial growth factor (VEGF), and the Wnt have been shown to enhance androgen receptor signaling and promote development of hormone-independent/castration-resistance in preclinical models [128, 129]. Moreover, the increased expression of the androgen receptor transcript was critical for tumor cells resistance to anti-androgen therapy . In this regard, inhibitors of cell cycle regulatory proteins has become an area of increased interest in targeting both cancer cells per se and a subpopulation of stem cell-like that initiates and maintains tumor growth, metastasis, and resistance to therapy .
Recently, we have demonstrated that Phenoxodiol induces DNA damage in different types of prostate cancer cell lines (DU145, LNCaP, and PC3), leading to the activation and cleavage of PARP-1 as well as the onset of the cell death program . Interesting, the expression of PARP-1 is highly expressed in LNCaP cells before and after treatment with H2O2 . Also accompanying Phenoxodiol-induced cell death we observed a reduction in the availability of NAD+, which potentially compromises ATP production via glycolysis . A major component of the injury is the alteration of membrane permeability caused by decreased activity of ATP-dependent ionic pumps . Massive NAD+ depletion is lethal in cells that divide rapidly and have a high-energy requirement. Since the three prostate cancer cell lines, LNCaP, PC3, and DU145 have high metastatic potential and are very resistance to several antitumoral drugs and radiation-induced apoptosis, the fact that this synthetic analogue of Genistein induces death in this tumor type, strongly suggested that this synthetic drug may be a useful treatment for metastatic prostate tumors . A recent study has reported that decreased PSA production and the expression of the androgen receptor in LNCaP cells were observed following a combined treatment with curcumin and isoflavones. Similarly, modulation of PSA levels was observed in a cohort of patients that received prostate biopsies . Finally, cannabidol and the synthetic cannabinoid WIN-55,212 were also determinant in inhibit proliferation and cleavage of PARP-1, caspase-3, as well as activation of phosphatases, and pro-apoptotic phosphatase on LNCaP cells. These compounds also exhibited antitumorigenic activity against different types of tumors and are now being tested in clinical trials for the treatment of brain tumors [135, 136]. The modulation of specific phos-phatases in the LNCaP cell line suggested the potential antitumorigenic activity of cannabi-noids against the treatment of prostate cancers .
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