Despite progress in understanding molecular aberrations that contribute to the development and progression of ovarian cancer,virtually all patients succumb to drug resistant disease at relapse.Emerging data implicate ...Despite progress in understanding molecular aberrations that contribute to the development and progression of ovarian cancer,virtually all patients succumb to drug resistant disease at relapse.Emerging data implicate bioactive sphingolipids and regulation of sphingolipid metabolism as components of response to chemotherapy or development of resistance.Increases in cytosolic ceramide induce apoptosis in response to therapy with multiple classes of chemotherapeutic agents.Aberrations in sphingolipid metabolism that accelerate the catabolism of ceramide or that prevent the production and accumulation of ceramide contribute to resistance to standard of care platinum-and taxane-based agents.The aim of this review is to highlight current literature and research investigating the influence of the sphingolipids and enzymes that comprise the sphingosine-1-phosphate pathway on the progression of ovarian cancer.The focus of the review is on the utility of sphingolipid-centric therapeutics as a mechanism to circumvent drug resistance in this tumor type.展开更多
Aggressive malignancies are characterized by relatively uncontrolled cell proliferation making them especially reliant on topoisomerase enzymes to enable high rates of DNA replication and transcription.DNA topoisomera...Aggressive malignancies are characterized by relatively uncontrolled cell proliferation making them especially reliant on topoisomerase enzymes to enable high rates of DNA replication and transcription.DNA topoisomerases resolve topological problems associated with DNA replication and other essential cellular processes involving DNA,such as transcription and recombination^([1]).As such,they are important targets for anti-cancer therapeutics.Further,understanding of topoisomerase biology is important for unraveling the mechanistic basis for resistance to many widely used anti-cancer drugs,such as doxorubicin,etoposide,and topotecan,for which DNA topoisomerases are established targets.Interestingly,several drugs that are not considered to directly target topoisomerase enzymes,such as the nucleoside analogs 5-FU and AraC,and those in development such as the polymeric fluoropyrimidine CF10^([2]),also affect the function of topoisomerases.展开更多
基金Waardenburg RCAM is supported by DoD OCRP pilot grant W81XWH-15-1-0198This work was supported by Faculty Development Grant from University of Alabama at Birmingham,Comprehensive Cancer Center(P30 CA013148).
文摘Despite progress in understanding molecular aberrations that contribute to the development and progression of ovarian cancer,virtually all patients succumb to drug resistant disease at relapse.Emerging data implicate bioactive sphingolipids and regulation of sphingolipid metabolism as components of response to chemotherapy or development of resistance.Increases in cytosolic ceramide induce apoptosis in response to therapy with multiple classes of chemotherapeutic agents.Aberrations in sphingolipid metabolism that accelerate the catabolism of ceramide or that prevent the production and accumulation of ceramide contribute to resistance to standard of care platinum-and taxane-based agents.The aim of this review is to highlight current literature and research investigating the influence of the sphingolipids and enzymes that comprise the sphingosine-1-phosphate pathway on the progression of ovarian cancer.The focus of the review is on the utility of sphingolipid-centric therapeutics as a mechanism to circumvent drug resistance in this tumor type.
基金van Waardenburg RCAM in part funded by American Cancer Society UAB ACS-IRG Junior Faculty Development Grant(ACS-IRG-60-001-53)Department of Defense OCRP pilot award W81XWH-15-1-0198+2 种基金the National Institutes of Health Cancer Center Core Support Grant(P30CA013148)National Institutes of Health-National Institute of Disorders and Stroke(1R21NS116312-01A1)Gmeiner WH in part supported by the National Cancer Institute Cancer Center Support Grant(P30CA012197)issued to the Wake Forest Baptist Comprehensive Cancer Center and National Institutes of Health-National Cancer Institute R21 CA218933.
文摘Aggressive malignancies are characterized by relatively uncontrolled cell proliferation making them especially reliant on topoisomerase enzymes to enable high rates of DNA replication and transcription.DNA topoisomerases resolve topological problems associated with DNA replication and other essential cellular processes involving DNA,such as transcription and recombination^([1]).As such,they are important targets for anti-cancer therapeutics.Further,understanding of topoisomerase biology is important for unraveling the mechanistic basis for resistance to many widely used anti-cancer drugs,such as doxorubicin,etoposide,and topotecan,for which DNA topoisomerases are established targets.Interestingly,several drugs that are not considered to directly target topoisomerase enzymes,such as the nucleoside analogs 5-FU and AraC,and those in development such as the polymeric fluoropyrimidine CF10^([2]),also affect the function of topoisomerases.
