Cancer multidrug resistance(MDR)impairs the therapeutic efficacy of various chemotherapeutics.Novel approaches,particularly the development of MDR reversal agents,are critically needed to address this challenge.This s...Cancer multidrug resistance(MDR)impairs the therapeutic efficacy of various chemotherapeutics.Novel approaches,particularly the development of MDR reversal agents,are critically needed to address this challenge.This study demonstrates that tenacissoside I(TI),a compound isolated from Marsdenia tenacissima(Roxb.)Wight et Arn,traditionally used in clinical practice as an ethnic medicine for cancer treatment,exhibits significant MDR reversal effects in ABCB1-mediated MDR cancer cells.TI reversed the resistance of SW620/AD300 and KBV200 cells to doxorubicin(DOX)and paclitaxel(PAC)by downregulating ABCB1 expression and reducing ABCB1 drug transport function.Mechanistically,protein arginine methyltransferase 1(PRMT1),whose expression correlates with poor prognosis and shows positive association with both ABCB1 and EGFR expressions in tumor tissues,was differentially expressed in TI-treated SW620/AD300 cells.SW620/AD300 and KBV200 cells exhibited elevated levels of EGFR asymmetric dimethylarginine(aDMA)and enhanced PRMT1-EGFR interaction compared to their parental cells.Moreover,TI-induced PRMT1 downregulation impaired PRMT1-mediated aDMA of EGFR,PRMT1-EGFR interaction,and EGFR downstream signaling in SW620/AD300 and KBV200 cells.These effects were significantly reversed by PRMT1 overexpression.Additionally,TI demonstrated resistance reversal to PAC in xenograft models without detectable toxicities.This study establishes TI's MDR reversal effect in ABCB1-mediated MDR human cancer cells through inhibition of PRMT1-mediated aDMA of EGFR,suggesting TI's potential as an MDR modulator for improving chemotherapy outcomes.展开更多
Therapeutic antibodies of targeting the programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1)pathway are used in hepatocellular carcinoma(HCC)treatment,but are limited by low response rates and immune...Therapeutic antibodies of targeting the programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1)pathway are used in hepatocellular carcinoma(HCC)treatment,but are limited by low response rates and immune-related toxicity[1].Searching for treatment approaches to combine with PD-1/PD-L1 blockade may potentially enhance the efficacy of PD-1/PD-L1 blockade and reduce its side effects.展开更多
Colorectal cancer(CRC)is the third most prevalent malignancy worldwide and the second leading cause of cancer-associated deaths,posing a significant threat to human health.Given the limited therapeutic options and poo...Colorectal cancer(CRC)is the third most prevalent malignancy worldwide and the second leading cause of cancer-associated deaths,posing a significant threat to human health.Given the limited therapeutic options and poor prognosis associated with CRC,there is an urgent need to develop new targeted therapeutic strategies to enhance clinical outcomes.The ubiquitin–proteasome system(UPS),a central regulator for cellular protein homeostasis,plays a pivotal role in the initiation and progression of CRC.The UPS modulates several essential signaling pathways and is involved in regulating tumor immunity and resistance to chemotherapy.Thus,the UPS contributes significantly to the complex biological processes underlying CRC pathogenesis.In recent years,small-molecule compounds targeting the UPS have exhibited considerable therapeutic potential in CRC treatment.These drugs intervene in crucial steps in the UPS,such as the activity of E1,E2,and E3 enzymes,or directly target the proteasome,thereby regulating the degradation of oncogenic proteins and effectively impeding tumor progression.Moreover,emerging therapeutic strategies such as proteolysis-targeting chimera(PROTAC)and molecular glue technologies selectively degrade specific oncogenic proteins,thereby offering new avenues and promising opportunities for CRC treatment.展开更多
The phosphatidylinositol 3-kinase(PI3K) pathway is frequently activated in human cancers.Class I PI3 Ks are lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate(PIP2) at the 3-OH of the inositol ring...The phosphatidylinositol 3-kinase(PI3K) pathway is frequently activated in human cancers.Class I PI3 Ks are lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate(PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate(PIP3), which in turn activates Akt and the downstream effectors like mammalian target of rapamycin(m TOR) to play key roles in carcinogenesis. Therefore, PI3 K has become an important anticancer drug target, and currently there is very high interest in the pharmaceutical development of PI3 K inhibitors. Idelalisib has been approved in USA and Europe as the first-in-class PI3 K inhibitor for cancer therapy. Dozens of other PI3 K inhibitors including BKM120 and ZSTK474 are being evaluated in clinical trials. Multifaceted studies on these PI3 K inhibitors are being performed, such as single and combinational efficacy, resistance, biomarkers,etc. This review provides an introduction to PI3 K and summarizes key advances in the development of PI3 K inhibitors.展开更多
Fetal hydrops is a rare but serious fetal developmental abnormality characterized by the abnormal accumulation of large amounts of fluid in the fetus resulting in generalized edema,and clinically manifested by abnorma...Fetal hydrops is a rare but serious fetal developmental abnormality characterized by the abnormal accumulation of large amounts of fluid in the fetus resulting in generalized edema,and clinically manifested by abnormal functioning of multiple organs and systems.1 The ryanodine receptor 1(RYR1)gene encodes the ryanodine receptor found in skeletal muscle and is expressed predominantly in cardiac and skeletal muscle.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82274211 and 82474190)the Natural Science Foundation of Tianjin(Nos.24JCZDJC00120 and 24PTLYHZ00280)Liaoning Provincial Department of Education Basic Research Projects for Higher Education Institutions(No.LJ212510163021)。
文摘Cancer multidrug resistance(MDR)impairs the therapeutic efficacy of various chemotherapeutics.Novel approaches,particularly the development of MDR reversal agents,are critically needed to address this challenge.This study demonstrates that tenacissoside I(TI),a compound isolated from Marsdenia tenacissima(Roxb.)Wight et Arn,traditionally used in clinical practice as an ethnic medicine for cancer treatment,exhibits significant MDR reversal effects in ABCB1-mediated MDR cancer cells.TI reversed the resistance of SW620/AD300 and KBV200 cells to doxorubicin(DOX)and paclitaxel(PAC)by downregulating ABCB1 expression and reducing ABCB1 drug transport function.Mechanistically,protein arginine methyltransferase 1(PRMT1),whose expression correlates with poor prognosis and shows positive association with both ABCB1 and EGFR expressions in tumor tissues,was differentially expressed in TI-treated SW620/AD300 cells.SW620/AD300 and KBV200 cells exhibited elevated levels of EGFR asymmetric dimethylarginine(aDMA)and enhanced PRMT1-EGFR interaction compared to their parental cells.Moreover,TI-induced PRMT1 downregulation impaired PRMT1-mediated aDMA of EGFR,PRMT1-EGFR interaction,and EGFR downstream signaling in SW620/AD300 and KBV200 cells.These effects were significantly reversed by PRMT1 overexpression.Additionally,TI demonstrated resistance reversal to PAC in xenograft models without detectable toxicities.This study establishes TI's MDR reversal effect in ABCB1-mediated MDR human cancer cells through inhibition of PRMT1-mediated aDMA of EGFR,suggesting TI's potential as an MDR modulator for improving chemotherapy outcomes.
基金National Natural Science Foundation of China(Grant Nos.:82274154,82304792)Natural Science Foundation of Tianjin Municipality(GrantNos.:23JCzXJC00150+1 种基金23JCJQjC00040)China Postdoctoral Science Foundation(Grant Nos.:2023M732627,2024T170657).
文摘Therapeutic antibodies of targeting the programmed cell death protein 1(PD-1)/programmed death-ligand 1(PD-L1)pathway are used in hepatocellular carcinoma(HCC)treatment,but are limited by low response rates and immune-related toxicity[1].Searching for treatment approaches to combine with PD-1/PD-L1 blockade may potentially enhance the efficacy of PD-1/PD-L1 blockade and reduce its side effects.
基金supported by grants from the National Natural Science Foundation of China(82274211 and 82404927)China Postdoctoral Science Foundation(2025T181057).
文摘Colorectal cancer(CRC)is the third most prevalent malignancy worldwide and the second leading cause of cancer-associated deaths,posing a significant threat to human health.Given the limited therapeutic options and poor prognosis associated with CRC,there is an urgent need to develop new targeted therapeutic strategies to enhance clinical outcomes.The ubiquitin–proteasome system(UPS),a central regulator for cellular protein homeostasis,plays a pivotal role in the initiation and progression of CRC.The UPS modulates several essential signaling pathways and is involved in regulating tumor immunity and resistance to chemotherapy.Thus,the UPS contributes significantly to the complex biological processes underlying CRC pathogenesis.In recent years,small-molecule compounds targeting the UPS have exhibited considerable therapeutic potential in CRC treatment.These drugs intervene in crucial steps in the UPS,such as the activity of E1,E2,and E3 enzymes,or directly target the proteasome,thereby regulating the degradation of oncogenic proteins and effectively impeding tumor progression.Moreover,emerging therapeutic strategies such as proteolysis-targeting chimera(PROTAC)and molecular glue technologies selectively degrade specific oncogenic proteins,thereby offering new avenues and promising opportunities for CRC treatment.
文摘The phosphatidylinositol 3-kinase(PI3K) pathway is frequently activated in human cancers.Class I PI3 Ks are lipid kinases that phosphorylate phosphatidylinositol 4,5-bisphosphate(PIP2) at the 3-OH of the inositol ring to generate phosphatidylinositol 3,4,5-trisphosphate(PIP3), which in turn activates Akt and the downstream effectors like mammalian target of rapamycin(m TOR) to play key roles in carcinogenesis. Therefore, PI3 K has become an important anticancer drug target, and currently there is very high interest in the pharmaceutical development of PI3 K inhibitors. Idelalisib has been approved in USA and Europe as the first-in-class PI3 K inhibitor for cancer therapy. Dozens of other PI3 K inhibitors including BKM120 and ZSTK474 are being evaluated in clinical trials. Multifaceted studies on these PI3 K inhibitors are being performed, such as single and combinational efficacy, resistance, biomarkers,etc. This review provides an introduction to PI3 K and summarizes key advances in the development of PI3 K inhibitors.
基金funded by the Guangxi Science and Technology Department (China) (No.Guike AD23026025).
文摘Fetal hydrops is a rare but serious fetal developmental abnormality characterized by the abnormal accumulation of large amounts of fluid in the fetus resulting in generalized edema,and clinically manifested by abnormal functioning of multiple organs and systems.1 The ryanodine receptor 1(RYR1)gene encodes the ryanodine receptor found in skeletal muscle and is expressed predominantly in cardiac and skeletal muscle.
