Anticlusterin increases chemotherapy sensitivity in breast cancer cells

Combining antisense clusterin oligonucleotides or antibodies to clusterin with commonly used anticancer drugs appears to increase the latter's toxicity in breast cancer cells, according to an in vitro study by Spanish and Canadian researchers.

The anticlusterin approach also increases chemotherapy-induced cytotoxicity, even in the presence of glucocorticoids such as dexamethasone, which have been shown to inhibit such cytotoxicity, Dr. Maximino Redondo and colleagues report in Breast Cancer Research, published online on December 13.

Several recent reports suggest that clusterin expression is a prominent factor in the resistance of cancer cells to chemotherapy, Dr. Redondo, of the Hospital Costa del Sol in Málaga, Spain, and his colleagues point out. Another study, they add, indicates that glucocorticoids, commonly given to cancer patients to combat the adverse effects of chemotherapy, could in fact inhibit the effectiveness of chemotherapy.

Hypothesizing that clusterin might be among the genes responsible for the anti-apoptotic effect of glucocorticoids, the researchers explored the potential of inhibiting clusterin by analyzing the cytotoxic interactions between antisense clusterin oligonucleotides or antibodies to clusterin and such common breast cancer drugs as doxorubicin, paclitaxel, and tamoxifen. These drug combinations were studied in vitro using breast carcinoma cell lines MCF-7 and MDA-MB-231.

In both cell lines, antisense clusterin treatment inhibited clusterin expression and caused significant decreases in cancer cell viability, and the same treatment significantly increased the cytotoxicity of paclitaxel and doxorubicin. A "significant additive cytotoxic effect" also resulted from combining antisense clusterin oligonucleotides or antibodies to clusterin with tamoxifen.

Their research showed that pretreatment with dexamethasone significantly decreased the effects of doxorubicin and paclitaxel. However, the antisense oligonucleotides countered this protective effect, increasing chemotherapy-induced cytotoxicity even in the presence of the glucocorticoid.

Clinical trials using antisense oligonucleotides to clusterin have already begun, Dr. Redondo told Reuters Health. These trials use OGX-011, an antisense oligonucleotide developed in the laboratory of co-author Dr. Martin Gleave and currently produced by Oncogene X Technologies in Vancouver, Canada.

Dr. Redondo added that prostate cancer patients tolerated this intravenous oligonucleotide well during the first phase 1 clinical trial. The therapy is currently in phase 2 clinical trials investigating the potential to improve treatment outcomes for patients with prostate cancer, non-small-cell lung cancer and breast cancer.