OBJECTIVE To investigate the pharmacological effect of a plant sesquiterpene lactone(designated D)and its semi-organically synthesized novel derivative(designated S)and the role of lipid mediators,viz.,oxylipins in at...OBJECTIVE To investigate the pharmacological effect of a plant sesquiterpene lactone(designated D)and its semi-organically synthesized novel derivative(designated S)and the role of lipid mediators,viz.,oxylipins in attenuating vemurafenib-induced cutaneous side effects.METHODS A DMBA/TPAinduced skin carcinogenesis mouse model mimicking cutaneous side effect caused by vemurafenib was established to evaluate the efficacy of compound D and S in reversal of vemurafenib side effect.Comparative oxylipin metabolomics platform using UPLC-TQD mass spectrometry coupled with partial least squares-discriminant analysis(PLS-DA)analysis,cell-based assays,and immunochemistry analysis were performed to elucidate the mechanism insights of DET and S compounds and the role of specific oxylipins in skin cancer carcinogenesis.RESULTS Vemurafenib treatment expedited the skin papillomas formation in DMBA-TPA treated mouse from week 6 to week 3.Both D and S compounds could suppress the vemurafenib side effect and also decrease total papillomas numbers(55% to 72%)and average sizes(66% to 89%).Oxylipins metabolome analysis shows that specific arachidonic acid metabolites may play a role in vemurafenib-induced squamous cell carcinoma or keratoacanthomas formation in mouse skin that can be deregulated by D or S compound treatment.Notably,S compound can inhibit vemurafenib-induced paradoxical activation of MAP kinases in mouse skin or in NRAS mutant melanoma cells.CONCLUSION Our results indicate that plant sesquiterpene lactone D and its novel analog can reduce cutaneous side effect of vemurafenib through novel modes of action by inhibiting paradoxical activation of MAP kinases and de-regulating pro-inflammation mediators COX-2 and specific ecosanoid-type of oxylipins.This study may suggest a novel adjuvant therapy approach in treatment of BRAFV600 Emutant melanoma.展开更多
Melanoma is one of the most malignant skin tumors, whose high invasion is generally associated with BRAF gene mutation. Although new chemotherapeutic drugs, such as vemurafenib, have been developed to inhibit the grow...Melanoma is one of the most malignant skin tumors, whose high invasion is generally associated with BRAF gene mutation. Although new chemotherapeutic drugs, such as vemurafenib, have been developed to inhibit the growth of melanoma, these drugs are usually administered intravenously or orally, resulting in toxic side effects on major tissues and organs. Tetrahedral framework nucleic acids(tFNAs) are a novel type of DNA nanostructures with excellent biocompatibility and versatility which have been proven to penetrate through skin barrier with ease. In this study, we prepared t FNAs with vemurafenib and connected DNA aptamer AS1411 at the apex of t FNAs(AS1411-tFNAs/vemurafenib). On one hand, AS1411-tFNAs/vemurafenib could kill melanoma cells by blocking the mutated BRAF gene in vitro. Compared with free vemurafenib, AS1411-tFNAs/vemurafenib had no obvious toxicity to normal cells. On the other hand,AS1411-tFNAs could transfer vemurafenib to cross through the skin barrier and permeate into tumor tissues. In vivo, transdermal delivery of AS1411-t FNAs/vemurafenib could inhibit the growth of human A375melanoma, whose inhibiting effect was stronger than intravenous administration of vemurafenib. These results demonstrated the application prospects of tFNAs combined with chemotherapeutic drugs in skin tumors.展开更多
Melanoma is the most serious type of skin cancer and one of the most common cancers in the world.Advanced melanoma is often resistant to conventional therapies and has high potential for metastasis and low survival ra...Melanoma is the most serious type of skin cancer and one of the most common cancers in the world.Advanced melanoma is often resistant to conventional therapies and has high potential for metastasis and low survival rates.Vemurafenib is a small molecule inhibitor of the BRAF serine-threonine kinase recently approved by the United States Food and Drug Administration to treat patients with metastatic and unresectable melanomas that carry an activating BRAF(V600E)mutation.Many clinical trials evaluating other therapeutic uses of vemurafenib are still ongoing.The ATP-binding cassette(ABC)transporters are membrane proteins with important physiological and pharmacological roles.Collectively,they transport and regulate levels of physiological substrates such as lipids,porphyrins and sterols.Some of them also remove xenobiotics and limit the oral bioavailability and distribution of many chemotherapeutics.The overexpression of three major ABC drug transporters is the most common mechanism for acquired resistance to anticancer drugs.In this review,we highlight some of the recent findings related to the effect of ABC drug transporters such as ABCB1 and ABCG2 on the oral bioavailability of vemurafenib,problems associated with treating melanoma brain metastases and the development of acquired resistance to vemurafenib in cancers harboring the BRAF(V600E)mutation.展开更多
In this research,a density functional theory(DFT)calculation was performed for investigation adsorption behavior of the anticancer drug Vemurafenib on BNNT(5,5-9)by using the M06-2X/6-31 G*level of theory in the solve...In this research,a density functional theory(DFT)calculation was performed for investigation adsorption behavior of the anticancer drug Vemurafenib on BNNT(5,5-9)by using the M06-2X/6-31 G*level of theory in the solvent water.The electronic spectra of the Vemurafenib drug,BNNT(5,5-9)and complex BNNT(5,5-9)/Vemurafenib in solvent water were calculated by Time Dependent Density Functional Theory(TD-DFT)for the study of adsorption effect.The non-bonded interaction effects of the Vemurafenib drug with BNNT(5,5-9)on the electronic properties,natural charges and chemical shift tensors have been also detected.The results display the change in title parameters after process adsorption.According to the natural bond orbital(NBO)results,the molecule Vemurafenib and BNNT(5,5-9)play as both electron donor and acceptor at the complex BNNT(5,5-9)/Vemurafenib.On the other hand,the charge transfer occurs between the bonding,antibonding or nonbonding orbitals in two molecules drug and BNNT.As a consequence,BNNT(5,5-9)can be considered as a drug delivery system for the transportation of Vemurafenib as anticancer drug within the biological systems.展开更多
目的:应用体外人肝微粒体及重组人源代谢酶孵育体系观察维罗非尼对尿苷二磷酸葡萄糖醛酸基转移酶1A1(UDP-glucuronosyltransferases,UGT1A1)介导的伊立替康代谢的抑制作用,通过体外-体内外推( in vitro-in vivo extrapolation,IV-IVE)...目的:应用体外人肝微粒体及重组人源代谢酶孵育体系观察维罗非尼对尿苷二磷酸葡萄糖醛酸基转移酶1A1(UDP-glucuronosyltransferases,UGT1A1)介导的伊立替康代谢的抑制作用,通过体外-体内外推( in vitro-in vivo extrapolation,IV-IVE)预测体内药物-药物相互作用(drug-drug interaction,DDI)的发生风险。方法:以混合人肝微粒体(human liver microsomes,HLMs)及重组表达的人UGT1A1 作为酶源,观察维罗非尼对UGT1A1介导的伊立替康活性代谢产物SN-38葡糖醛酸化反应的抑制作用,求得半数最大抑制浓度(half maximum inhibitory concentration,IC 50 )和抑制动力学常数 K i及抑制类型;并基于体外参数预测了体内维罗非尼与伊立替康联合应用引发的潜在DDI风险。结果:维罗非尼对UGT1A1具有较强的非竞争性抑制作用,IC 50 为 4.35 μmol/L, K i为 9.77 μmol/L。口服治疗剂量的维罗非尼(960 mg,每日两次)可导致SN-38的药时曲线下面积(area under the curve,AUC)增加7%~149%。结论:维罗非尼与伊立替康联合应用时,可通过强效抑制UGT1A1而影响伊立替康在体内的代谢清除,具有引发DDI的风险。展开更多
Metastatic melanoma has long been considered to have a very poor prognosis and to be chemo-resistant. However, a subgroup of patients with metastatic melanoma presents remarkable responses to chemotherapeutic agents, ...Metastatic melanoma has long been considered to have a very poor prognosis and to be chemo-resistant. However, a subgroup of patients with metastatic melanoma presents remarkable responses to chemotherapeutic agents, even in the absence of a response to modern targeted therapies and immunotherapies; accordingly, determining predictive biomarkers of the response to chemotherapies for metastatic melanoma remains a priority to guide treatment in these patients. We report a case study of a patient with B-Raf proto-oncogene serine/threonine kinase-mutated metastatic melanoma harbouring many genetic mutations. The patient did not respond to prior targeted therapies or immunotherapies but experienced a dramatic objective radiological and clinical response to subsequent dacarbazine-based chemotherapy. In the era of targeted therapies and immunotherapies for metastatic melanoma, cytotoxic chemotherapies may still represent an interesting therapeutic weapon in a well-deined subgroup of patients presenting with speciic genetic and molecular features.展开更多
Introduction Melanoma is the fifth most common cancer in the United States.The estimated number of new cases of melanoma in 2012 is 76,250, with 9,180 melanoma-related death[1,2].Moreover,the incidence of melanoma is ...Introduction Melanoma is the fifth most common cancer in the United States.The estimated number of new cases of melanoma in 2012 is 76,250, with 9,180 melanoma-related death[1,2].Moreover,the incidence of melanoma is rising faster than any other cancer in man and second only to lung cancer in women[3].Although only 5% of patients had metastatic disease on diagnosis, the median overall survival (OS) is less than one-year and the twoyear survival rate is between 10~20%[4,5].Compared to the white population, Asian population is less prone to this condition because of the protective effect of melanin[6].The overall incidence of melanoma in China has not been reported.A recent single institution study in China reported 522 melanoma cases during only four years from 2006~2010[7].展开更多
Objective:The BRAF inhibitor,vemurafenib,has been widely used in the treatment of patients with melanoma-bearing BRAFV600E mutations.While the initial response to vemurafenib is usually excellent,the majority of patie...Objective:The BRAF inhibitor,vemurafenib,has been widely used in the treatment of patients with melanoma-bearing BRAFV600E mutations.While the initial response to vemurafenib is usually excellent,the majority of patients eventually develop resistance and metastatic disease.However,the underlying molecular mechanism remains elusive.The objective of this study was therefore to identify additional molecular targets responsible for vemurafenib resistance.Methods:Western blots and immunohistochemistry analyses were used to evaluate expressions of PYK2 and p-PYK2 in cultured cells and melanoma tissue microarrays.The relationships of p-PYK2 with clinicopathological parameters were statistically analyzed.Invadopodia cell invasion,and a Ca2+assay were used to determine the effect of vemurafenib resistance-induced p-PYK2 on melanoma progression.A mouse model was used to assess the effects of PYK2 on melanoma metastasis.Results:Elevated p-PYK2 levels were detected in vemurafenib-resistant melanoma cells,and PYK2 was shown to regulate invadopodia formation in melanoma cells.Vemurafenib triggered invadopodia formation by activation of PYK2.Inhibition of PYK2 with either shRNA or the small molecule inhibitor,PF562711,dramatically reduced vemurafenib-induced invadopodia formation.Furthermore,knockdown of PYK2 significantly reduced melanoma lung metastasis in vivo.Increased expressions of p-PYK2 in melanoma patients were positively correlated with advanced stage(P=0.002),metastasis(P<0.001),and Clark grade(P<0.001),and were also associated with short overall survival[hazard ratio(HR)=3.304,P=0.007]and progression-free survival(HR=2.930,P=0.001).Conclusions:PYK2 mediated vemurafenib-induced melanoma cell migration and invasion.Inhibition of PYK2 resensitized melanoma cells to vemurafenib.Phospho-PYK2 was a prognostic biomarker in melanoma patients.展开更多
基金The project supported by a research grant from Ministry of Science and Technology(MOST 103-2320-B-001-008-MY3),Chinese Taipei
文摘OBJECTIVE To investigate the pharmacological effect of a plant sesquiterpene lactone(designated D)and its semi-organically synthesized novel derivative(designated S)and the role of lipid mediators,viz.,oxylipins in attenuating vemurafenib-induced cutaneous side effects.METHODS A DMBA/TPAinduced skin carcinogenesis mouse model mimicking cutaneous side effect caused by vemurafenib was established to evaluate the efficacy of compound D and S in reversal of vemurafenib side effect.Comparative oxylipin metabolomics platform using UPLC-TQD mass spectrometry coupled with partial least squares-discriminant analysis(PLS-DA)analysis,cell-based assays,and immunochemistry analysis were performed to elucidate the mechanism insights of DET and S compounds and the role of specific oxylipins in skin cancer carcinogenesis.RESULTS Vemurafenib treatment expedited the skin papillomas formation in DMBA-TPA treated mouse from week 6 to week 3.Both D and S compounds could suppress the vemurafenib side effect and also decrease total papillomas numbers(55% to 72%)and average sizes(66% to 89%).Oxylipins metabolome analysis shows that specific arachidonic acid metabolites may play a role in vemurafenib-induced squamous cell carcinoma or keratoacanthomas formation in mouse skin that can be deregulated by D or S compound treatment.Notably,S compound can inhibit vemurafenib-induced paradoxical activation of MAP kinases in mouse skin or in NRAS mutant melanoma cells.CONCLUSION Our results indicate that plant sesquiterpene lactone D and its novel analog can reduce cutaneous side effect of vemurafenib through novel modes of action by inhibiting paradoxical activation of MAP kinases and de-regulating pro-inflammation mediators COX-2 and specific ecosanoid-type of oxylipins.This study may suggest a novel adjuvant therapy approach in treatment of BRAFV600 Emutant melanoma.
基金supported by National Key R&D Program of China (No.2019YFA0110600)National Natural Science Foundation of China (No.81970916)+3 种基金Sichuan Science and Technology Program(No.2022NSFSC0002)Sichuan Province Youth Science and Technology Innovation Team (No.2022JDTD0021)Research and Develop ProgramWest China Hospital of Stomatology Sichuan University (No.RD03202302)。
文摘Melanoma is one of the most malignant skin tumors, whose high invasion is generally associated with BRAF gene mutation. Although new chemotherapeutic drugs, such as vemurafenib, have been developed to inhibit the growth of melanoma, these drugs are usually administered intravenously or orally, resulting in toxic side effects on major tissues and organs. Tetrahedral framework nucleic acids(tFNAs) are a novel type of DNA nanostructures with excellent biocompatibility and versatility which have been proven to penetrate through skin barrier with ease. In this study, we prepared t FNAs with vemurafenib and connected DNA aptamer AS1411 at the apex of t FNAs(AS1411-tFNAs/vemurafenib). On one hand, AS1411-tFNAs/vemurafenib could kill melanoma cells by blocking the mutated BRAF gene in vitro. Compared with free vemurafenib, AS1411-tFNAs/vemurafenib had no obvious toxicity to normal cells. On the other hand,AS1411-tFNAs could transfer vemurafenib to cross through the skin barrier and permeate into tumor tissues. In vivo, transdermal delivery of AS1411-t FNAs/vemurafenib could inhibit the growth of human A375melanoma, whose inhibiting effect was stronger than intravenous administration of vemurafenib. These results demonstrated the application prospects of tFNAs combined with chemotherapeutic drugs in skin tumors.
基金CP Wu was supported by funds from National Science Council of Taiwan(Grant No.NSC102-2320-B-182-036)S.V.Ambudkar was supported by the Intramural Research Program of the National Institutes of Health,National Cancer Institute.National Cancer Institute,NIH,Center for Cancer Research.
文摘Melanoma is the most serious type of skin cancer and one of the most common cancers in the world.Advanced melanoma is often resistant to conventional therapies and has high potential for metastasis and low survival rates.Vemurafenib is a small molecule inhibitor of the BRAF serine-threonine kinase recently approved by the United States Food and Drug Administration to treat patients with metastatic and unresectable melanomas that carry an activating BRAF(V600E)mutation.Many clinical trials evaluating other therapeutic uses of vemurafenib are still ongoing.The ATP-binding cassette(ABC)transporters are membrane proteins with important physiological and pharmacological roles.Collectively,they transport and regulate levels of physiological substrates such as lipids,porphyrins and sterols.Some of them also remove xenobiotics and limit the oral bioavailability and distribution of many chemotherapeutics.The overexpression of three major ABC drug transporters is the most common mechanism for acquired resistance to anticancer drugs.In this review,we highlight some of the recent findings related to the effect of ABC drug transporters such as ABCB1 and ABCG2 on the oral bioavailability of vemurafenib,problems associated with treating melanoma brain metastases and the development of acquired resistance to vemurafenib in cancers harboring the BRAF(V600E)mutation.
基金supported by the National Academy of Sciences of Belarus。
文摘In this research,a density functional theory(DFT)calculation was performed for investigation adsorption behavior of the anticancer drug Vemurafenib on BNNT(5,5-9)by using the M06-2X/6-31 G*level of theory in the solvent water.The electronic spectra of the Vemurafenib drug,BNNT(5,5-9)and complex BNNT(5,5-9)/Vemurafenib in solvent water were calculated by Time Dependent Density Functional Theory(TD-DFT)for the study of adsorption effect.The non-bonded interaction effects of the Vemurafenib drug with BNNT(5,5-9)on the electronic properties,natural charges and chemical shift tensors have been also detected.The results display the change in title parameters after process adsorption.According to the natural bond orbital(NBO)results,the molecule Vemurafenib and BNNT(5,5-9)play as both electron donor and acceptor at the complex BNNT(5,5-9)/Vemurafenib.On the other hand,the charge transfer occurs between the bonding,antibonding or nonbonding orbitals in two molecules drug and BNNT.As a consequence,BNNT(5,5-9)can be considered as a drug delivery system for the transportation of Vemurafenib as anticancer drug within the biological systems.
文摘目的:应用体外人肝微粒体及重组人源代谢酶孵育体系观察维罗非尼对尿苷二磷酸葡萄糖醛酸基转移酶1A1(UDP-glucuronosyltransferases,UGT1A1)介导的伊立替康代谢的抑制作用,通过体外-体内外推( in vitro-in vivo extrapolation,IV-IVE)预测体内药物-药物相互作用(drug-drug interaction,DDI)的发生风险。方法:以混合人肝微粒体(human liver microsomes,HLMs)及重组表达的人UGT1A1 作为酶源,观察维罗非尼对UGT1A1介导的伊立替康活性代谢产物SN-38葡糖醛酸化反应的抑制作用,求得半数最大抑制浓度(half maximum inhibitory concentration,IC 50 )和抑制动力学常数 K i及抑制类型;并基于体外参数预测了体内维罗非尼与伊立替康联合应用引发的潜在DDI风险。结果:维罗非尼对UGT1A1具有较强的非竞争性抑制作用,IC 50 为 4.35 μmol/L, K i为 9.77 μmol/L。口服治疗剂量的维罗非尼(960 mg,每日两次)可导致SN-38的药时曲线下面积(area under the curve,AUC)增加7%~149%。结论:维罗非尼与伊立替康联合应用时,可通过强效抑制UGT1A1而影响伊立替康在体内的代谢清除,具有引发DDI的风险。
文摘Metastatic melanoma has long been considered to have a very poor prognosis and to be chemo-resistant. However, a subgroup of patients with metastatic melanoma presents remarkable responses to chemotherapeutic agents, even in the absence of a response to modern targeted therapies and immunotherapies; accordingly, determining predictive biomarkers of the response to chemotherapies for metastatic melanoma remains a priority to guide treatment in these patients. We report a case study of a patient with B-Raf proto-oncogene serine/threonine kinase-mutated metastatic melanoma harbouring many genetic mutations. The patient did not respond to prior targeted therapies or immunotherapies but experienced a dramatic objective radiological and clinical response to subsequent dacarbazine-based chemotherapy. In the era of targeted therapies and immunotherapies for metastatic melanoma, cytotoxic chemotherapies may still represent an interesting therapeutic weapon in a well-deined subgroup of patients presenting with speciic genetic and molecular features.
文摘Introduction Melanoma is the fifth most common cancer in the United States.The estimated number of new cases of melanoma in 2012 is 76,250, with 9,180 melanoma-related death[1,2].Moreover,the incidence of melanoma is rising faster than any other cancer in man and second only to lung cancer in women[3].Although only 5% of patients had metastatic disease on diagnosis, the median overall survival (OS) is less than one-year and the twoyear survival rate is between 10~20%[4,5].Compared to the white population, Asian population is less prone to this condition because of the protective effect of melanin[6].The overall incidence of melanoma in China has not been reported.A recent single institution study in China reported 522 melanoma cases during only four years from 2006~2010[7].
基金supported by National Natural Science Foundation of China(Grant Nos.81871990 and 31671448)Yunnan Applicative and Basic Research Program(Grant Nos.2019FY003030 and 202101AV070002)a grant(2019KF006)from Conservation and Utilization of Bio-Resources in Yunnan(YNCUB).
文摘Objective:The BRAF inhibitor,vemurafenib,has been widely used in the treatment of patients with melanoma-bearing BRAFV600E mutations.While the initial response to vemurafenib is usually excellent,the majority of patients eventually develop resistance and metastatic disease.However,the underlying molecular mechanism remains elusive.The objective of this study was therefore to identify additional molecular targets responsible for vemurafenib resistance.Methods:Western blots and immunohistochemistry analyses were used to evaluate expressions of PYK2 and p-PYK2 in cultured cells and melanoma tissue microarrays.The relationships of p-PYK2 with clinicopathological parameters were statistically analyzed.Invadopodia cell invasion,and a Ca2+assay were used to determine the effect of vemurafenib resistance-induced p-PYK2 on melanoma progression.A mouse model was used to assess the effects of PYK2 on melanoma metastasis.Results:Elevated p-PYK2 levels were detected in vemurafenib-resistant melanoma cells,and PYK2 was shown to regulate invadopodia formation in melanoma cells.Vemurafenib triggered invadopodia formation by activation of PYK2.Inhibition of PYK2 with either shRNA or the small molecule inhibitor,PF562711,dramatically reduced vemurafenib-induced invadopodia formation.Furthermore,knockdown of PYK2 significantly reduced melanoma lung metastasis in vivo.Increased expressions of p-PYK2 in melanoma patients were positively correlated with advanced stage(P=0.002),metastasis(P<0.001),and Clark grade(P<0.001),and were also associated with short overall survival[hazard ratio(HR)=3.304,P=0.007]and progression-free survival(HR=2.930,P=0.001).Conclusions:PYK2 mediated vemurafenib-induced melanoma cell migration and invasion.Inhibition of PYK2 resensitized melanoma cells to vemurafenib.Phospho-PYK2 was a prognostic biomarker in melanoma patients.
