Molecular Chemotherapy and Chemotherapy: A New Front against Late-Stage Hormone-Refractory Prostate Cancer

Abstract

Purpose: Stemming from its inherent heterogeneity, single-agent treatments are essentially ineffective against castration-resistant prostate cancer (CRPC). Thus, clinically relevant regimens that harness different modalities to maximize treatment efficacy without increasing cumulative toxicities are urgently needed. Based on this rationale, we investigated whether a novel combination of purine nucleoside phosphorylase–mediated, gene-directed enzyme-prodrug therapy (PNP-GDEPT) with docetaxel against CRPC has superior efficacy in comparison with individual treatments. Methods: The in vitro cell growth inhibition in differentially treated murine and human CRPC cell lines was established using a cell-viability assay. The extent of synergy, additivity, or antagonism between treatments was evaluated using CalcuSyn statistical analyses. The local and systemic effects of docetaxel and/or PNP-GDEPT were tested in both immunodeficient and immunocompetent mice against human and murine CRPC tumors, respectively. Subsequently, immunohistochemical analyses and an evaluation of serum cytokine and serum toxicity profiles were conducted to characterize the differential host responses to treatment. Results: The combined use of PNP-GDEPT and docetaxel led to strong synergistic cell killing in vitro. Compared with the individual modalities, a combination of the 2 led to a marked reduction in “local and distant” tumor growth in vivo, and importantly, with lowered doses and without additional toxicities. Immunomodulation was indicated by enhanced immune cell infiltration and altered serum cytokine levels. Furthermore, a lowering of T-helper type 2 cytokines, MCP-1, interleukin (IL)-4, IL-6, and IL-10 marked lower tumor burden and enhanced treatment efficacy. Conclusion: PNP-GDEPT and docetaxel are a potent combination against CRPC in immunocompetent and immunodeficient settings; these outcomes have implications of translational potential for improved treatment and management of CRPC patients. Clin Cancer Res; 17(12); 4006–18. ©2011 AACR.

Antitumor activity of IL-32β through the activation of lymphocytes, and the inactivation of NF-κB and STAT3 signals

“…42 Furthermore, lowering the level of IL-6 was found to be critical for antitumor activity against prostate cancer by combined purine nucleoside phosphorylase and docetaxel by increasing lymphocyte infiltration, and modulating cytokine levels. 43 We found that tumor-promoting proinflammatory cytokines (IL-1 β , IL-6, and TNF- α ) were decreased, but levels of tumor growth-inhibitory cytokine IL-10 were elevated in spleen and tumor tissues. Concomitantly, we also found that IL-32 β mice, and IL-32 β C and IL-32 β p nude mice had higher levels of CD8 + T cells and CD57 + NK cells in tumor tissues, blood, spleen, and thymus than nontransgenic mice and IL-32 β v mice.…”

DTX3L and ARTD9 inhibit IRF1 expression and mediate in cooperation with ARTD8 survival and proliferation of metastatic prostate cancer cells

“…In order to investigate whether constitutive overexpression of DTX3L, ARTD8 and ARTD9 is associated with mPCa we analyzed their expression levels in the PCa cell lines PC3, DU145 and LNCaP [54-59], and in the normal prostate luminal epithelial cell lines HPE and RWPE1. PC3 and DU145 cells are androgen-refractory mPCa cell lines and are commonly used as CRPC models [60-62]. PC3 and DU145 cells have a high and moderate tumorigenic potential, respectively [58-62], and are highly invasive compared to the poorly tumorigenic LNCaP cells [62-65].…”

The Role of Hypoxia-Inducible Factor 1α in Determining the Properties of Castrate-Resistant Prostate Cancers

“…The two widely used PC cell lines PC3 and DU145 are not considered as fully representative of CRPC cells since they were not isolated from prostate cancers that had relapsed after androgen deprivation therapy, and since they express little [5] if any AR [6], whereas AR is often over-expressed in CRPC tumors. However as PC3 and DU145 cells display some of the fundamental properties of a CRPC tumor including high migration (metastasis), androgen-independence and chemo-resistance similar to the CRPC cell line LNCaP C4-2 [7], and also share similar molecular properties, including depletion/mutation of mitochondrial DNA, which have been correlated with invasiveness and drug resistance [8], these two cell lines are frequently referred to as CRPC cells [9], [10], [11].…”