Inhibition of bladder cancer development by allyl isothiocyanate

Abstract

Bladder cancer is one of the common human cancers and also has a very high recurrence rate. There is a great need for agents capable of inhibiting bladder cancer development and recurrence. Here, we report that allyl isothiocyanate (AITC), an ingredient of many common cruciferous vegetables, potently inhibited the proliferation of bladder carcinoma cell lines in vitro [half maximal inhibitory concentration (IC(50)) of 2.7-3.3 microM], which was associated with profound G(2)/M arrest and apoptosis. In contrast, AITC was markedly less toxic to normal human bladder epithelial cells (IC(50) of 69.4 microM). AITC was then evaluated in two rat bladder cancer models in vivo (an orthotopic model and a subcutaneous model). The orthotopic model closely mimics human bladder cancer development and recurrence. We show that a low oral dose of AITC (1 mg/kg) significantly inhibited the development and muscle invasion of the orthotopic bladder cancers but was ineffective against the subcutaneous xenografts of the same cancer cells in the same animals. This differential effect was explained by our finding that urinary levels of AITC equivalent were two to three orders of magnitude higher than that in the plasma and that its levels in the orthotopic cancer tissues were also three orders of magnitude higher than that in the subcutaneous cancer tissues. Moreover, we show that AITC is a multi-targeted agent against bladder cancer. In conclusion, AITC is selectively delivered to bladder cancer tissue through urinary excretion and potently inhibits bladder cancer development and invasion.

Allyl isothiocyanate triggers G2/M phase arrest and apoptosis in human brain malignant glioma GBM 8401 cells through a mitochondria-dependent pathway

“…flow cytometric analysis and DAPI staining was applied to confirm cell apoptosis in examined GBM 8401 cells. These results corroborate findings of other studies on several different cancer cell lines (34,(36)(37)(38)42). Furthermore, apoptotic cell death is a genetically regulated biological process and it can be divided into extrinsic and intrinsic signaling major pathways (43,44).…”

Animal Models for Basic and Preclinical Research in Bladder Cancer

“…As previously mentioned, there are examples showing that different results are observed when the tumor is inoculated subcutaneously or orthotopically in the bladder. In studies of chemoprevention, inhibition of bladder cancer development by allyl isothiocyanate was detected for tumors growing orthotopically but not in the subcutis (Bhattacharya et al, 2010). Furthermore, as described in the previous section, considerable variation has been detected between the two models in assays of immunotherapy, angiogenesis, invasion and metastatic spread, among others.…”

“…Studies of carcinogenic substances or prevention of carcinogenesis may be carried out in animal models. Also, analysis of the response to cytotoxicity and immunotherapy treatments can be performed (Bhattacharya et al, 2010;Takeuchi et al, 2011;Zhang et al, 2011). cells are stably transfected with genes coding for fluorescent proteins (Tanaka et al, 2003) or enzymes catalyzing bioluminescence (Hadaschik et al, 2007), allowing for the continuous visualization of tumor development after intravesical instillation of tumor cells.…”

“…Intensive research in bladder cancer, as well as that in most tumors, is being carried out to elucidate the reason for the appearance of tumors, and to find out which factors are involved in their development and which are related to the tumor progression process. These investigations, which provide insights into the biology of the tumor, are essential for the implementation of new therapeutic and/or preventive modalities (Bhattacharya et al, 2010;Zhang et al, 2011). Research on basic science is focused on the mechanisms that lead cells towards transformation and development of cancer, using simple experimental models where it is easier to interpret the results.…”

Cruciferous Vegetables: Dietary Phytochemicals for Cancer Prevention

“…Extensive epidemiological studies revealed repeatedly an inverse relationship between cruciferous vegetable consumption and the incidence of cancer at a number of sites (Ambrosone et al, 2004;Joseph et al, 2004;Zhao et al, 2007;Lam et al, 2009;Bhattacharya et al, 2010). Isothiocyanates, derived from the hydrolysis of glucosinolates, are believed to mediate the chemopreventive effect of these vegetables.…”