N-Hydroxyapiosporamide(N-hydap),a marine product derived from a sponge-associated fungus,has shown promising inhibitory effects on small cell lung cancer(SCLC).However,there is limited understanding of its metabolic p...N-Hydroxyapiosporamide(N-hydap),a marine product derived from a sponge-associated fungus,has shown promising inhibitory effects on small cell lung cancer(SCLC).However,there is limited understanding of its metabolic pathways and characteristics.This study explored the in vitro metabolic profiles of N-hydap in human recombinant cytochrome P450s(CYPs)and UDP-glucuronosyltransferases(UGTs),as well as human/rat/mice microsomes,and also the pharmacokinetic properties by HPLC-MS/MS.Additionally,the cocktail probe method was used to investigate the potential to create drug-drug interactions(DDIs).N-Hydap was metabolically unstable in various microsomes after 1 h,with about 50%and 70%of it being eliminated by CYPs and UGTs,respectively.UGT1A3 was the main enzyme involved in glucuronidation(over 80%),making glucuronide the primary metabolite.Despite low bioavailability(0.024%),N-hydap exhibited a higher distribution in the lungs(26.26%),accounting for its efficacy against SCLC.Administering N-hydap to mice at normal doses via gavage did not result in significant toxicity.Furthermore,N-hydap was found to affect the catalytic activity of drug metabolic enzymes(DMEs),particularly increasing the activity of UGT1A3,suggesting potential for DDIs.Understanding the metabolic pathways and properties of N-hydap should improve our knowledge of its drug efficacy,toxicity,and potential for DDIs.展开更多
The efficient clinical treatment of oral squamous cell carcinoma(OSCC)is still a challenge that demands the development of effective new drugs.Phenformin has been shown to produce more potent anti-tumor activities tha...The efficient clinical treatment of oral squamous cell carcinoma(OSCC)is still a challenge that demands the development of effective new drugs.Phenformin has been shown to produce more potent anti-tumor activities than metformin on different tumors,however,not much is known about the influence of phenformin on OSCC cells.We found that phenformin suppresses OSCC cell proliferation,and promotes OSCC cell autophagy and apoptosis to significantly inhibit OSCC cell growth both in vivo and in vitro.RNA-seq analysis revealed that autophagy pathways were the main targets of phenformin and identified two new targets DDIT4(DNA damage inducible transcript 4)and NIBAN1(niban apoptosis regulator 1).We found that phenformin significantly induces the expression of both DDIT4 and NIBAN1 to promote OSCC autophagy.Further,the enhanced expression of DDIT4 and NIBAN1 elicited by phenformin was not blocked by the knockdown of AMPK but was suppressed by the knockdown of transcription factor ATF4(activation transcription factor 4),which was induced by phenformin treatment in OSCC cells.Mechanistically,these results revealed that phenformin triggers endoplasmic reticulum(ER)stress to activate PERK(protein kinase R-like ER kinase),which phosphorylates the transitional initial factor eIF2,and the increased phosphorylation of eIF2 leads to the increased translation of ATF4.In summary,we discovered that phenformin induces its new targets DDIT4 and especially NIBAN1 to promote autophagic and apoptotic cell death to suppress OSCC cell growth.Our study supports the potential clinical utility of phenformin for OSCC treatment in the future.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82274002,42376124)Marine Economy Development Project of Guangdong Province(GDNRC[2021]52)+1 种基金Hainan Provincial Natural Science Foundation of China(823CXTD393)Key-Area Research and Development Program of Guangdong Province(2023B1111050008)。
文摘N-Hydroxyapiosporamide(N-hydap),a marine product derived from a sponge-associated fungus,has shown promising inhibitory effects on small cell lung cancer(SCLC).However,there is limited understanding of its metabolic pathways and characteristics.This study explored the in vitro metabolic profiles of N-hydap in human recombinant cytochrome P450s(CYPs)and UDP-glucuronosyltransferases(UGTs),as well as human/rat/mice microsomes,and also the pharmacokinetic properties by HPLC-MS/MS.Additionally,the cocktail probe method was used to investigate the potential to create drug-drug interactions(DDIs).N-Hydap was metabolically unstable in various microsomes after 1 h,with about 50%and 70%of it being eliminated by CYPs and UGTs,respectively.UGT1A3 was the main enzyme involved in glucuronidation(over 80%),making glucuronide the primary metabolite.Despite low bioavailability(0.024%),N-hydap exhibited a higher distribution in the lungs(26.26%),accounting for its efficacy against SCLC.Administering N-hydap to mice at normal doses via gavage did not result in significant toxicity.Furthermore,N-hydap was found to affect the catalytic activity of drug metabolic enzymes(DMEs),particularly increasing the activity of UGT1A3,suggesting potential for DDIs.Understanding the metabolic pathways and properties of N-hydap should improve our knowledge of its drug efficacy,toxicity,and potential for DDIs.
基金supported by the National Natural Science Foundations of China(82273554,82073470)the Shandong Provincial Key R&D Program(ZR2019ZD36).
文摘The efficient clinical treatment of oral squamous cell carcinoma(OSCC)is still a challenge that demands the development of effective new drugs.Phenformin has been shown to produce more potent anti-tumor activities than metformin on different tumors,however,not much is known about the influence of phenformin on OSCC cells.We found that phenformin suppresses OSCC cell proliferation,and promotes OSCC cell autophagy and apoptosis to significantly inhibit OSCC cell growth both in vivo and in vitro.RNA-seq analysis revealed that autophagy pathways were the main targets of phenformin and identified two new targets DDIT4(DNA damage inducible transcript 4)and NIBAN1(niban apoptosis regulator 1).We found that phenformin significantly induces the expression of both DDIT4 and NIBAN1 to promote OSCC autophagy.Further,the enhanced expression of DDIT4 and NIBAN1 elicited by phenformin was not blocked by the knockdown of AMPK but was suppressed by the knockdown of transcription factor ATF4(activation transcription factor 4),which was induced by phenformin treatment in OSCC cells.Mechanistically,these results revealed that phenformin triggers endoplasmic reticulum(ER)stress to activate PERK(protein kinase R-like ER kinase),which phosphorylates the transitional initial factor eIF2,and the increased phosphorylation of eIF2 leads to the increased translation of ATF4.In summary,we discovered that phenformin induces its new targets DDIT4 and especially NIBAN1 to promote autophagic and apoptotic cell death to suppress OSCC cell growth.Our study supports the potential clinical utility of phenformin for OSCC treatment in the future.
