Sensitivity Of Chemotherapy Drugs Research Articles

Hedgehog signaling regulates drug sensitivity by targeting ABC transporters ABCB1 and ABCG2 in epithelial ovarian cancer

A major challenge of successful chemotherapy in ovarian cancer is overcoming intrinsic or acquired multi-drug resistance caused by active drug efflux mediated by ATP-binding cassette (ABC) transporters. Regulation of these transporters in ovarian cancer is poorly understood. We have found that abnormal expression of the hedgehog (Hh) signaling pathway transcription factor Gli1 is involved in the regulation of ABC transporters ABCB1 and ABCG2 in ovarian cancer. Hh is a known regulator of cancer cell proliferation and differentiation in several other types of invasive and metastatic malignancies. Our work has demonstrated that Gli1 is abnormally activated in a portion of ovarian cancers. Inhibition of Gli1 expression decreases ABCB1 and ABCG2 gene expression levels and enhances the response of ovarian cancer cells to certain chemotherapeutic drugs. The underlying mechanism is a direct association of Gli1 with a specific consensus sequence located in the promoter region of ABCB1 and ABCG2 genes. This study provides new understanding of ABC gene regulation by Hh signaling pathway, which may lead to the identification of new markers to detect and to anticipate ovarian cancer chemotherapy drug sensitivity.

Abstract 3068: Hedgehog signaling regulates drug sensitivity by targeting ABC transporters in epithelial ovarian cancer (EOC)

Abstract A major challenge of successful chemotherapy in treatment of ovarian cancer is overcoming intrinsic or acquired multi-drug resistance caused mostly by the active efflux mediated by ATP-binding cassette (ABC) transporters. The regulation of these transporters in ovarian cancer is poorly understood. Our research shows that in ovarian cancer, abnormal regulation of the hedgehog (Hh) signaling pathway is involved in regulation of ABC transporters. Hh is a known regulator of cancer cell proliferation and differentiation in several other types of invasive and metastatic malignancies. Our work on Gli1, a key Hh downstream signaling gene, has shown frequent activation of the Hh pathway in ovarian cancer. Inhibition of the Hh signaling pathway by inhibitors or Gli1 siRNA increases ABC gene expression levels and the response of ovarian cancer cells to certain chemotherapeutic drugs. The mechanism underlying is a direct association of Gli1 with a specific consensus sequence located in the promoter region of ABC genes. This study provides new information in the knowledge of ABC gene regulation and will contribute to generating new targets/markers to detect and anticipate ovarian cancer patient chemotherapy drug sensitivity which could lead to more effective treatments and improved survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3068. doi:1538-7445.AM2012-3068

“Overcoming breast cancer drug resistance with mTOR inhibitors”. Could it be a myth or a real possibility in the short-term future?

The mTOR pathway is pivotal not only in tumorigenesis but also in chemotherapy and hormonal drug sensitivity. It is clear that improvements in using new targeted therapies are required to improve breast cancer (BC) outcome. Nevertheless, to achieve this, new molecular biomarkers are required to define the potential sensitivity or resistance of cancer cells. By targeting the mTOR pathway, several critical central transduction pathways that sustain BC are abrogated (HER-2/Neu and the estrogen receptor pathway). Thus, the compounds that inhibit mTOR have a double mechanism of toxicity on BC cells when used in combination with a currently used drug: (1) overcoming primary drug resistance and (2) restoring sensitivity when resistance arises after long-term exposure. This review covers the utility of inhibitors of the mTOR pathway in BC and emphasizes the new paradigm of close symbiosis between oncology and molecular biology to better profiling and treating BC with a targeted approach. In particular, we focused on the new drug RAD001 (Everolimus) due to the great results from preclinical and clinical trials make it the most hopeful compound among mTOR inhibitors for the treatment of BC.

Glycogen synthase kinase-3 and tumorigenesis

It has recently been demonstrated that Glycogen synthase kinase-3β (GSK-3β) plays an important role in tumorigenesis through its regulation of tumor cell growth via a variety of mechanisms. In some tumors, activation of GSK-3β inhibits the growth of tumor cells whereas in other tumors, GSK-3β promotes tumor cells growth, meanwhile, GSK-3β may also regulate sensitivity of chemotherapy drugs to tumor cells,thus GSK-3β is likely to become a novel target for tumor therapy. Key words: Glycogen synthase kinase-3β; Neoplasms

Correlation between chemosensitivity testing and expression of P-gp,LRP in esophageal carcinoma cell cultured in vitro

Objective To study the correlation between chemotherapy drug sensitivity and the expression of P-glycoprotein protein(P-gp),lung resistant-related protein(LRP)in different esophageal carcinoma patients,which will offer experimental evidence for clinical individualized chemotherapy of esophageal carcinoma patients.Methods Selected fresh esophageal carcinoma's tissue,Common used drugs and chemoscheme for esophageal carcinoma were used for chemosensitivity testing of the primary cultured tumor cells.At the same time,immunohistochemistry method was used to detect the expression of P-gp and LRP of esophageal carcinoma cells.Results The chemotherapy drug sensitivity of single drug was different(P＜0.05).The combination of Tax and DDP had the best effect.DDP and NVB combination had a better effect than DDP and 5-FU combination.The sensitivity of DDP had no significant correlations with expression intensity of P-gp(P＞0.05),and it had significant correlation with expression intensity of LRP(P＜0.05).There were significant correlations between sensitivity of both NVB group and Tax group and expression intensity of P-gp and LRP(P＜0.05).There was no significant correlations between sensitivity of 5-FU and expression intensity of P-gp and LRP(P＞0.05).Conclusion The esophageal carcinoma chemosensitivity in vitro can indicate the sensitive drug of different patients,and guide individualized chemotherapy.The expression of P-gp and LRP has relationship with several chemotherapy drugs,which can provide base for individualized chemotherapy in clinic. Key words: Esophageal neoplasms; Tumor cells,cultured; Antineoplastic agent; P-glyeoprotein; Lung resistant-related protein