The pharmacological impact of ABCB1 and ABCG2 overexpression on the anticancer effect of LDC000067 in human cancer cells.
| Autor: | Ming Lu Lin, 林明露 |
|---|---|
| Rok vydání: | 2016 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 104 The serine/threonine cycline-dependent kinase 9 (CDK 9) is a critical elongation factor for RNA polymerase II-directed transcription, which is necessary for cancer cell survival. CDK 9 is an important therapeutic target that inhibits cancer cell proliferation by stop RNA synthesis and regulation of p53 by phosphorylation. LDC000067 is a novel and potent small molecule compound that can selectively inhibit the activity of CDK 9. Unfortunately, alike most chemotherapeutic agents, the effectiveness of risk of LDC000067 can be hampered by development of acquired resistance in cancer cells that prone to present a significant resistance challenge. One of the most common mechanisms for acquired resistance in cancer chemotherapy is associated with the overexpression of ATP-binding cassette (ABC) transporters ABCB1 or ABCG2. In this study, we reveal that ABCB1 and ABCG2 reduce the intracellular accumulation of LDC000067 and confer significant resistance to LDC000067, which lead to reduced activity of LDC000067 to inhibit RNA synthesis and regulation of p53 in human cancer cells. Moreover, we discovered that ABCB1 or ABCG2 overexpressing cancer cells and cells transfected with ABCB1 or ABCG2 were significantly less sensitive to LDC000067. More significantly, we found that by inhibiting the function of ABCB1 or ABCG2, the reduced apoptosis and sensitivity to LDC000067 treatment in ABCB1 or ABCG2 overexpressing cells can be restored. Taken together, our finding indicated that ABCB1 and/or ABCG2-mediated acquired resistance to LDC000067, but we can consider to combined ABCB1 and/or ABCG2 inhibitor as a potential treatment strategy in the clinic. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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