In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 5669-5669
Abstract:
Prostate Cancer (PC) is one of the most common cancers in American men, especially as they age. Although PC initially responds to androgen therapy, as the cancer progresses it usually becomes androgen-independent and prone to metastasis and multi-drug resistance, which kills the majority of patients within 5 years of diagnosis. Therefore, it is necessary to develop better therapeutic strategies which could prevent both early and late stage PC. Our recent studies demonstrate that Aldose Reductase (AR) is the main mediator of inflammatory signals induced by growth factors, cytokines, chemokines, carcinogens etc. Since inflammation is known to play a central role in PC, we investigated the possible role of AR in heterogenous androgen-dependent, -independent, and multi-drug resistant PC cells. Using androgen -dependent LNCaP and -independent PC-3 cells, we have determined the effect of AR inhibition on growth factors such as IGF- and EGF -induced proliferation, cell cycle progression, and generation of reactive oxygen species (ROS). We also determined the effect of AR inhibition on the phosphorylation/expression of androgen receptor, PSA, AKT/PI3K, NF-kB etc in PC cells. Our results show that inhibition of AR by fidarestat significantly prevented the IGF -and EGF-induced proliferation and generation of ROS in both androgen -dependent (LNCaP) and -independent (PC3) PC cells. Cell cycle analysis suggested that inhibition of AR prevents IGF-induced entry of cells from G1 to S phase in PC3 cells. Inhibition of AR also prevented IGF-induced activation of AKT/PI3K and NF-kB. Results with androgen-dependent LNCaP cells showed that inhibition of AR prevented the phosphorylation of androgen receptor, and secretion and expression of PSA when cells were cultured in 5% serum. Further, inhibition of AR increased the drug-sensitivity of multi-drug-resistant PC3 cells against chemotherapeutic agents such as cisplatin, docetaxel, doxorubicin, and methotrexate. These results indicate that AR mediates oxidative stress -induced inflammatory signals in prostate carcinogenesis. Hence, AR inhibition could be a potential therapeutic target against prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5669.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM10-5669
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2010
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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