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Simple Summary: Prostate cancer is one of topmost health concerns, and metastatic castration-resistant prostate cancer is the fatal form. Two taxanes, docetaxel and cabazitaxel, are the only two FDA-approved chemotherapeutics that can provide survival benefits to patients with the lethal version of prostate cancer. Taxanes, alongside numerous other naturally occurring products, can promote the assembly and stability of microtubules to halt cell division and promote various cancer cell deaths. Additionally, this group of compounds, named microtubule stabilizing agents, can impede the androgen–androgen receptor complex from moving into the cell nucleus, conquering androgen receptor-containing prostate cancer cell proliferation and metastasis. This review aims to overview the preclinical and clinical studies, clinical uses, and the mechanisms of action of microtubule-stabilizing agents as anti-prostate cancer agents. A variety of microtubule-stabilizing cytotoxic agents (MSA) with diverse chemical scaffolds have been discovered from marine sponges, microorganisms, and plants. Two MSAs, docetaxel and cabazitaxel, are the exclusive chemotherapeutics that convey a survival benefit in patients with castration-resistant prostate cancer (CRPC). Additional MSAs have been investigated for their potential in treating prostate cancer in both clinical and preclinical settings. Independent of promoting mitotic arrest, MSAs can suppress the nuclear accumulation of androgen receptor (AR), which is the driving force for prostate cancer cell growth and progression. The alternative mechanism not only helps to better understand the clinical efficacy of docetaxel and cabazitaxel for AR-driven CRPC but also provides an avenue to seek better treatments for various forms of prostate cancer. The dual mechanisms of action enable MSAs to suppress AR-null prostate cancer cell proliferation by cell mitosis pathway and to interfere with the AR signaling pathway in AR positive cells. MSA chemotherapeutics, being administered alone or in combination with other therapeutics, may serve as the optimal therapeutic option for patients with either castration-sensitive or castration-resistant prostate cancer. This review provides an overview of the anti-prostate cancer profiles (including preclinical and clinical studies, and clinical use) of diverse MSAs, as well as the mechanism of action. [ABSTRACT FROM AUTHOR]

Background: Ionizing radiation (IR) is a mainstay of cancer therapy, but irradiation can at times also lead to stress responses, which counteract IR-induced cytotoxicity. IR also triggers cellular secretion of vascular endothelial growth factor, transforming growth factor β and matrix metalloproteinases, among others, to promote tumor progression. Lysyl oxidase is known to play an important role in hypoxia-dependent cancer cell dissemination and metastasis. Here, we investigated the effects of IR on the expression and secretion of lysyl oxidase (LOX) from tumor cells. Methods: LOX-secretion along with enzymatic activity was investigated in multiple tumor cell lines in response to irradiation. Transwell migration assays were performed to evaluate invasive capacity of naïve tumor cells in response to IR-induced LOX. In vivo studies for confirming IR-enhanced LOX were performed employing immunohistochemistry of tumor tissues and ex vivo analysis of murine blood serum derived from locally irradiated A549-derived tumor xenografts. Results: LOX was secreted in a dose dependent way from several tumor cell lines in response to irradiation. IR did not increase LOX-transcription but induced LOX-secretion. LOX-secretion could not be prevented by the microtubule stabilizing agent patupilone. In contrast, hypoxia induced LOX-transcription, and interestingly, hypoxia-dependent LOX-secretion could be counteracted by patupilone. Conditioned media from irradiated tumor cells promoted invasiveness of naïve tumor cells, while conditioned media from irradiated, LOX- siRNA-silenced cells did not stimulate their invasive capacity. Locally applied irradiation to tumor xenografts also increased LOX-secretion in vivo and resulted in enhanced LOX-levels in the murine blood serum. Conclusions: These results indicate a differential regulation of LOX-expression and secretion in response to IR and hypoxia, and suggest that LOX may contribute towards an IR-induced migratory phenotype in sublethally-irradiated tumor cells and tumor progression. [ABSTRACT FROM AUTHOR]

Background: Ionizing radiation (IR) in combination with microtubule stabilizing agents (MSA) is a promising combined treatment modality. Supra-additive treatment responses might result from direct tumor cell killing and cooperative indirect, tumor cell-mediated effects on the tumor microenvironment. Here we investigated deregulation of matrix metalloproteinase (MMP) activity, as an important component of the tumor microenvironment, by the combined treatment modality of IR with the clinically relevant MSA patupilone. Methods: Expression, secretion and activity of MMPs and related tissue inhibitors of metalloproteinases (TIMPs) were determined in cell extracts and conditioned media derived from human fibrosarcoma HT1080 and human glioblastoma U251 tumor cells in response to treatment with IR and the MSA patupilone. Treatment-dependent changes of the invasive capacities of these tumor cell lines were analysed using a Transwell invasion assay. Control experiments were performed using TIMP-directed siRNA and TIMP-directed inhibitory antibodies. Results: Enzymatic activity of secreted MMPs was determined after treatment with patupilone and irradiation in the human fibrosarcoma HT1080 and the human glioblastoma U251 tumor cell line. IR enhanced the activity of secreted MMPs up to 2-fold and cellular pretreatment with low dose patupilone (0.05-0.2 nM) counteracted specifically the IR-induced MMP activity. The cell invasive capacity of HT1080 and U251 cells was increased after irradiation with 2 Gy by 30% and 50%, respectively, and patupilone treatment completely abrogated IR-induced cell invasion. Patupilone did not alter the level of MMP expression, but interestingly, the protein level of secreted TIMP-1 and TIMP-2 was lower after combined treatment than after irradiation treatment alone. Furthermore, siRNA depletion of TIMP-1 or TIMP-2 prevented IR-mediated induction of MMP activity and cell invasion. Conclusions: These results indicate that patupilone counteracts an IR-induced MMP activation process by the reduction of secreted TIMP-1 and TIMP-2 proteins, which are required for activation of MMPs. Since IR-induced MMP activity could contribute to tumor progression, treatment combination of IR with patupilone might be of great clinical benefit for tumor therapy. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: The metabolic switch to aerobic glycolysis (Warburg effect) and enhanced lactate production is characteristic for aggressive tumor cells and is a co-determining factor for tumor response and treatment outcome. Thus analysis of the metabolic status under treatment is important to understand and improve treatment modalities. Materials and methods: Metabolite concentrations were determined by the immersion of tumor sections in an ATP, lactate or glucose-depending luciferase-containing buffer system. Integrated light output is detected in a bioluminescent detection system. Results: Mice carrying tumor xenografts derived from A549 lung cancer cells were treated with the microtubule stabilizing agent patupilone, ionizing radiation or in combination. Lactate levels were significantly reduced and glucose levels drastically increased in comparison to untreated tumors. Interestingly, these changes were only minimal in tumors derived from patupilone-resistant but otherwise isogenic A549EpoB40 cells. ATP levels of all tumors tested did not change under any treatment. When compared with histological endpoints, basal and treatment-dependent changes of lactate levels in the different tumors mainly correlated with the proliferative activity and the tumor growth response to treatment. Conclusions: This study shows that the tumor metabolism is responsive to different treatment modalities and could eventually be used as an early surrogate marker for treatment response. [Copyright &y& Elsevier]