Clusterin (4. Cancer)

The acquisition of resistance to a wide variety of proapototic stimuli was initially demonstrated by introducing the clusterin gene into prostate cancer cells. Furthermore, silencing clusterin expression using antisepse oligodeoxynucle­otides (AS ODN) synergistically enhanced the effects of several conventional therapeutic modalities through the effective induction of apoptosis in prostate cancer xenograft models. Based on these outcomes, Phase i clinical trials were conducted using As clusterin ODN incorporating 2‘-O-(2-methoxy)ethylgapmer backbone (OGX-011), and the optimal dose of OGX-011 capable of inducing </= 90% suppression of clusterin in human prostate cancer tissue was determined. Collectively, these findings suggest the utility of inactivating clusterin function using AS ODN technology as a novel therapeutic strategy for prostate cancer treatment. There have been four kinds of Phase II studies that have begun to further evaluate the efficacy of OGX-011 in patients with prostate, breast and lung cancers ^Ref .
Clusterin protein was present in the cytoplasm of cervical cancer cells. The expression of clusterin protein in invasive cervical cancer tissues was not related to any clinicopathologic factors analyzed. Patients with positive clusterin expression showed significantly worse prognosis than those with negative clusterin expression (p=0.017). Multivariate analysis including clusterin expression revealed that clusterin expression (p=0.006) and the number of positive node groups (p=0.002) were independent prognostic factors for survival. Survival of patients with invasive cervical cancer could be stratified into three groups by combination of clusterin expression and number of positive node groups with an estimated 5-year survival rate of 100.0% for no or one positive node group irrespective of clusterin expression (group A), 78.7% for multiple node groups with negative clusterin expression (group B), and 14.3% for multiple node groups with positive clusterin expression (group C) (p=0.03 for group A vs. group B, p=0.004 for group B vs. group C, and p<0.0001 for group A vs. group C). Clusterin expression and the number of positive node groups were independent prognostic factors for invasive cervical cancer patients treated with radical hysterectomy and systematic lymphadenectomy. Clusterin might be a new molecular marker to predict the survival of cervical cancer patients with multiple positive node groups ^Ref .

Overexpression of the apoptosis-related protein clusterin is associated with breast cancer development and tumor progression. Clusterin-specific antisense oligonucleotides and antibodies were used to sensitize breast carcinoma cells to anticancer drugs routinely used in breast cancer therapy. MCF-7 and MDA-MB-231 cells were treated with the oligonucleotide or antibody, chemotherapeutic agents (doxorubicin or paclitaxel), tamoxifen, or with combinations of these. Treatments that include antisense clusterin oligonucleotide or antibody to clusterin have been shown to reduce the number of viable cells more effectively than treatment with the drugs alone. It was also demonstrated that dexamethasone pretreatment of breast cancer cell lines inhibits chemotherapy-induced cytotoxicity and is associated with the transcriptional induction of clusterin. However, anticlusterin treatment increases chemotherapy-induced cytotoxicity, even in the presence of glucocorticoids, suggesting a possible role for these proteins in glucocorticoid-mediated survival. These data suggest that combined treatment with antibodies to clusterin or antisense clusterin oligodeoxynucle­otides and paclitaxel, doxorubicin, or tamoxifen could be a novel and attractive strategy to inhibit the progression of breast carcinoma by regulation of the clusterin function. Moreover, glucocorticoid activation in breast cancer cells regulates survival signaling by the direct transactivation of genes like clusterin which encode proteins that decrease susceptibility to apoptosis. Given the widespread clinical administration of dexamethasone before chemotherapy, understanding glucocorticoid-induced survival mechanisms is essential for achieving optimal therapeutic responses ^Ref .