Naringenin reduces lung metastasis in a breast cancer resection model

Metastasis is the main cause of death in cancer patients. To improve the outcomes of patients undergoing a surgery, new adjuvant therapies that can effectively inhibit metastases have to be developed. Studies have shown that flavonoid naringenin, a natural product that is mainly present in grapes and citrus, may contribute to cancer prevention. It has many advantages compared to traditional chemotherapeutic drugs, such as low toxicity. To determine whether naringenin can also inhibit metastases, a breast cancer resection model that mimics clinical situations was established. We found that orally administered naringenin significantly decreased the number of metastatic tumor cells in the lung and extended the life span of tumor resected mice. Flow cytometry analysis revealed that T cells displayed enhanced antitumor activity in naringenin treated mice, with an increased proportion of IFN-γ and IL-2 expressing T cells. In vitro studies further demonstrated that relief of immunosuppression caused by regulatory T cells might be the fundamental mechanism of metastasis inhibition by naringenin. These results indicate that orally administered naringenin can inhibit the outgrowth of metastases after surgery via regulating host immunity. Thus, naringenin can be an ideal surgical adjuvant therapy for breast cancer patients.

Addiction to protein kinase Cɩdue to PRKCI gene amplification can be exploited for an aptamer-based targeted therapy in ovarian cancer

PRKCI,the gene for protein kinase Cι(PKCι),is frequently amplified in ovarian cancer and recent studies have shown that PKCιparticipates in ovary tumorigenesis.However,it is unknown whether PKCιis differentially involved in the growth/survival between PRKCI-amplified and non-amplified ovarian cancer cells.In this study,we analyzed ovarian cancer patient dataset and revealed that PRKCI is the only PKC family member significantly amplified in ovarian cancer and PRKCI amplification is associated with higher PKCιexpression.Using a panel of ovarian cancer cell lines,we found that abundance of PKCιis generally associated with PRKCI amplification.Interestingly,silencing PKCιled to apoptosis in PRKCI-amplified ovarian cancer cells but not in those without PRKCI amplification,thus indicating an oncogenic addiction to PKCɩin PRKCI-amplified cells.Since small-molecule inhibitors characterized to selectively block atypical PKCs did not offer selectivity nor sensitivity in PRKCI-amplified ovarian cancer cells and were even cytotoxic to non-cancerous ovary surface or fallopian tube epithelial cells,we designed an EpCAM aptamer-PKCιsiRNA chimera(EpCAM-siPKCιaptamer).EpCAM-siPKCιaptamer not only effectively induced apoptosis of PRKCI-amplified ovarian cancer cells but also greatly deterred intraperitoneal tumor development in xenograft mouse model.This study has demonstrated a precision medicine-based strategy to target a subset of ovarian cancer that contains PRKCI amplification and shown that the EpCAM aptamerdelivered PKCιsiRNA may be used to suppress such tumors.