Prostate cancer (PCa) has a high incidence worldwide. One of the major causes of PCa resistance is intratumoral hypoxia. In solid tumors, hypoxia is strongly associated with malignant progression and resistance to therapy, which is an indicator of poor prognosis. The antiproliferative effect and induced death caused by doxorubicin, epirubicin, cisplatin, and flutamide in a hormone-independent PCa cell line will be evaluated. The hypoxia effect on drug resistance to these drugs, as well as cell proliferation and migration, will be also analyzed. All drugs induced an antiproliferative effect and also cell death in the cell line under study. Hypoxia made the cells more resistant to all drugs. Moreover, our results reveal that long time cell exposure to hypoxia decreases cellular proliferation and migration. Hypoxia can influence cellular resistance, proliferation, and migration. This study shows that hypoxia may be a key factor in the regulation of PCa. 1. Introduction Prostate cancer (PCa) is one of the most common diseases in the world, being the sixth leading cause of cancer death worldwide [1]. The incidence of PCa varies according to three major risk factors: age, ethnicity, and familial predisposition [2–6]. Hypoxia can be defined as a reduction in oxygen partial pressure (pO2). This characteristic constitutes a condition of various pathophysiological states such as ischemic vascular disease, myocardial infarction, stroke, respiratory insufficiency, and cancer [7]. Clinically relevant levels of hypoxia are detected in 50% to 60% of solid tumors [8]. Hypoxia results from an imbalance between rate of consumption and supply of oxygen to cancer cells, thus compromising several cellular functions. Cancer cells have the capacity to adapt to hypoxic environments due to various genetic and epigenetic mechanisms and alterations at cellular level that contribute to adaptive changes which lead to a clinically aggressive phenotype, having hypoxic tumors a poor prognosis. These tumors are more difficult to treat, being highly resistant, presenting an increased risk of recurrence and progression [9, 10]. Regarding PCa, intratumoral oxygen levels were evaluated through a polarographic electrode with the form of a needle, and it was found that pO2 in PCa was significantly lower (pO2 = 2.4？mmHg) than in normal tissues (muscle, pO2 = 30？mmHg) [11]. In fact, increase of hypoxia may be critical in PCa progression and resistance [12]. In this work, we aim at studying the antiproliferative effect and cell death induced by various agents of chemotherapy and hormonal
References
[1]
M. M. Center, A. Jemal, J. Lortet-Tieulent et al., “International variation in prostate cancer incidence and mortality rates,” European Urology, vol. 61, no. 6, pp. 1079–1092, 2012.
[2]
A. Leibovitz, Y. Baumoehl, and R. Segal, “Increased incidence of pathological and clinical prostate cancer with age: age related alterations of local immune surveillance,” Journal of Urology, vol. 172, no. 2, pp. 435–437, 2004.
[3]
R. Siegel, D. Naishadham, and A. Jemal, “Cancer statistics, 2012,” CA Cancer Journal for Clinicians, vol. 62, no. 1, pp. 10–29, 2012.
[4]
O. Cussenot, A. Valeri, P. Berthon, G. Fournier, and P. Mangin, “Hereditary prostate cancer and other genetic predispositions to prostate cancer,” Urologia Internationalis, vol. 60, no. 2, pp. 30–34, 1998.
[5]
C. A. Heinlein and C. Chang, “Androgen receptor in prostate cancer,” Endocrine Reviews, vol. 25, no. 2, pp. 276–308, 2004.
[6]
K. J. Pienta and P. S. Esper, “Risk factors for prostate cancer,” Annals of Internal Medicine, vol. 118, no. 10, pp. 793–803, 1993.
[7]
I. Papandreou, C. Krishna, F. Kaper, D. Cai, A. J. Giaccia, and N. C. Denko, “Anoxia is necessary for tumor cell toxicity caused by a low-oxygen environment,” Cancer Research, vol. 65, no. 8, pp. 3171–3178, 2005.
[8]
N. Chan, M. Milosevic, and R. G. Bristow, “Tumor hypoxia, DNA repair and prostate cancer regression: new targets and new therapies,” Future Oncology, vol. 3, no. 3, pp. 329–341, 2007.
[9]
A. M. Abrantes, M. E. Serra, D. Murtinho, A. R. Gonsalves, and M. F. Botelho, “An insight into tumoral hypoxia: the radiomarkers and clinical applications,” Oncology Reviews, vol. 3, no. 1, pp. 3–18, 2009.
[10]
A. M. Abrantes, E. Serra, C. Gon？alves et al., “Tumour hypoxia and technetium tracers: in vivo studies,” Current Radiopharmaceuticals, vol. 5, no. 2, pp. 99–105, 2012.
[11]
G. D. Stewart, J. A. Ross, D. B. McLaren, C. C. Parker, F. K. Habib, and A. C. P. Riddick, “The relevance of a hypoxic tumour microenvironment in prostate cancer,” BJU International, vol. 105, no. 1, pp. 8–13, 2010.
[12]
M. H？ckel and P. Vaupel, “Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects,” Journal of the National Cancer Institute, vol. 93, no. 4, pp. 266–276, 2001.
[13]
A. C. Mamede, A. S. Pires, A. M. Abrantes, et al., “Cytotoxicity of ascorbic acid in a human colorectal adenocarcinoma cell line (WiDr): in vitro and in vivo studies,” Nutrition and Cancer, vol. 64, pp. 1049–1057, 2012.
[14]
A. M. Abrantes, M. E. S. Serra, A. C. Gon？alves et al., “Hypoxia-induced redox alterations and their correlation with 99mTc-MIBI and 99mTc-HL-91 uptake in colon cancer cells,” Nuclear Medicine and Biology, vol. 37, no. 2, pp. 125–132, 2010.
[15]
P. Houghton, R. Fang, I. Techatanawat, G. Steventon, P. J. Hylands, and C. C. Lee, “The sulphorhodamine (SRB) assay and other approaches to testing plant extracts and derived compounds for activities related to reputed anticancer activity,” Methods, vol. 42, no. 4, pp. 377–387, 2007.
[16]
C. Liang, A. Y. Park, and J. Guan, “In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro,” Nature Protocols, vol. 2, no. 2, pp. 329–333, 2007.
[17]
A. F. Santos, H. Huang, and D. J. Tindall, “The androgen receptor: a potential target for therapy of prostate cancer,” Steroids, vol. 69, no. 2, pp. 79–85, 2004.
[18]
T. Gilligan and P. W. Kantoff, “Chemotherapy for prostate cancer,” Urology, vol. 60, no. 3, pp. 94–100, 2002.
[19]
D. J. Smith, M. Jaggi, W. Zhang et al., “Metallothioneins and resistance to cisplatin and radiation in prostate cancer,” Urology, vol. 67, no. 6, pp. 1341–1347, 2006.
[20]
T. Wakasugi, H. Izumi, T. Uchiumi et al., “ZNF143 interacts with p73 and is involved in cisplatin resistance through the transcriptional regulation of DNA repair genes,” Oncogene, vol. 26, no. 36, pp. 5194–5203, 2007.
[21]
M. P. Wirth, O. W. Hakenberg, and M. Froehner, “Antiandrogens in the treatment of prostate Cancer,” European Urology, vol. 51, no. 2, pp. 306–314, 2007.
[22]
L. Montalvo, M. J. Carmena, O. Bola？os, N. Rodríguez-Henche, M. Sánchez-Chapado, and J. C. Prieto, “Effects of the antiandrogen flutamide on the expression of protein kinase C isoenzymes in LNCaP and PC3 human prostate cancer cells,” Bioscience Reports, vol. 24, no. 1, pp. 11–21, 2004.
[23]
F. Al-Saeedi, “Effects of flutamide on [Methyl-3H]-Choline uptake in human prostate Cancer-3 cells: A Pilot Study,” Current Therapeutic Research, vol. 68, no. 4, pp. 226–241, 2007.
[24]
J. A. Watson, C. J. Watson, A. McCrohan et al., “Generation of an epigenetic signature by chronic hypoxia in prostate cells,” Human molecular genetics, vol. 18, no. 19, pp. 3594–3604, 2009.
[25]
L. J. Frederiksen, D. R. Siemens, J. P. Heaton, L. R. Maxwell, M. A. Adams, and C. H. Graham, “Hypoxia induced resistance to doxorubicin in prostate cancer cells is inhibited by low concentrations of glyceryl trinitrate,” Journal of Urology, vol. 170, no. 3, pp. 1003–1007, 2003.
[26]
N. Chen, X. Chen, R. Huang et al., “BCL-xL is a target gene regulated by hypoxia-inducible factor-1α,” The Journal of Biological Chemistry, vol. 284, no. 15, pp. 10004–10012, 2009.
[27]
L. Marignol, M. Coffey, M. Lawler, and D. Hollywood, “Hypoxia in prostate cancer: a powerful shield against tumour destruction?” Cancer Treatment Reviews, vol. 34, no. 4, pp. 313–327, 2008.
[28]
Y. Dai, K. Bae, and D. W. Siemann, “Impact of hypoxia on the metastatic potential of human prostate cancer Cells,” International Journal of Radiation Oncology Biology Physics, vol. 81, no. 2, pp. 521–528, 2011.
[29]
X. Xu, M. Mikhailova, Z. Chen et al., “Peptide from the C-terminal domain of tissue inhibitor of matrix metalloproteinases-2 (TIMP-2) inhibits membrane activation of matrix metalloproteinase-2 (MMP-2),” Matrix Biology, vol. 30, no. 7-8, pp. 404–412, 2011.
[30]
L. Yu and C. A. Hales, “Long-term exposure to hypoxia inhibits tumor progression of lung cancer in rats and mice,” BMC Cancer, vol. 11, article 331, 2011.
