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Protective autophagy by thymidine causes resistance to rapamycin in colorectal cancer cells in vitro

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Cancer Drug Resistance 2021年第3期4卷 719-727页

作者： I.V.Bijnsdorp godefridus j.peters Department of Medical Oncology Amsterdam UMClocation VUMC1007 MB AmsterdamNetherlands Department of Urology Amsterdam UMClocation VUMC1007 MB AmsterdamNetherlands Department of Biochemistry Medical University of Gdansk80-210 GdanskPoland

Aim:Thynidine phosphorylase(TP)acts as a proangiogenic growth factor which may regulate mammalian Target of Rapamycin(mTOR).We investigated whether the TP substrate thymidine and overexpression of TP affected mTOR signaling by comparing Colo320(TP deficient)cells and its TP-transfected variant(Colo320TP1).Methods:Drug resistance was assessed with the sulforhodamine B assay,protein expression with Western blotting,cell cycle distribution and cell death with Fluorescence-activated cell sorting analysis,and autophagy with ***:Colo320 and Colo320TP1 cells had comparable levels of sensitivity to the mTOR inhibitor *** treatment led to 13-and 50-fold resistance to rapamycin in Colo320 and Colo320TP1 cells,*** Colo320TP1 cells,the thymidine phosphorylase inhibitor(TPI)reversed the thymidine induced resistance to rapamycin,but not in Colo320 cells,indicating a role for TP in the *** increased p70/S6k-phosphorylation(downstream of mTOR)in Colo320TP1,but it was not affected in *** a mechanism behind resistance,we studied the levels of autophagy and found that,in Colo320TP1 cells,autophagy was highly induced by thymidine-rapamycin,which was decreased by *** addition,the autophagy inhibitor 3-methyl-adenine completely inhibited autophagy and its ***:Rapamycin resistance in TP-expressing cancer cells may therefore be related to thymidine-mediated autophagy activation.

关键词： Thymidine phosphorylase mTOR rapamycin thymidine thymidine phosphorylase inhibitor autophagy

Fungal mycobiome-mediated immune response:a non-negligible promoter in pancreatic oncogenesis and chemoresistance

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Cancer Drug Resistance 2023年第2期6卷 284-290页

作者： Yaling jiang Valentina Donati godefridus j.peters Elisa Giovannetti Dong Mei Deng Department of Preventive Dentistry Academic Center for Dentistry Amsterdam(ACTA)University of Amsterdam and Vrije Universiteit AmsterdamAmsterdam 1081 LANetherlands Department of Medical Oncology Amsterdam University Medical Centerslocation VUMCVrije Universiteit AmsterdamAmsterdam 1081 HVNetherlands Unit of Pathological Anatomy 2 Azienda Ospedaliero-Universitaria PisanaPisa 56100Italy Department of Biochemistry Medical University of GdanskGdansk 80-210Poland Fondazione Pisana per la Scienza ONLUS San Giuliano TermePisa 56017Italy

Pancreatic ductal adenocarcinoma(PDAC)is one of the most lethal cancers in humans due to late diagnosis and poor response to *** tumor microenvironment(TME)of PDAC is characterized by a distinctive,suppressive immune profile,which inhibits the protective functions of anti-tumor immunity and thereby contributes to PDAC ***,the study of Alam et *** for the first time that the intratumoral fungal mycobiome could contribute to the recruitment and activation of type 2 immune cells in the TME of PDAC via enhancing the secretion of a chemoattractant,interleukin(IL-)*** this article,we reviewed the important findings of this *** with our findings,we synthetically discussed the role of the fungal mycobiome in orchestrating the immune response and thereby modulating tumor progression.

关键词： Mycobiome pancreatic cancer chemoresistance interleukin 33 type 2 immune cells

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

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Cancer Drug Resistance 2018年第1期1卷 6-29页

作者： Adrian C.jaramillo Farah Al Saig jacqueline Cloos Gerrit jansen godefridus j.peters Department of Hematology VU University Medical CenterCancer Center AmsterdamAmsterdam 1007 MBThe Netherlands Department of Medical Oncology VU University Medical CenterCancer Center AmsterdamAmsterdam 1007 MBThe Netherlands Amsterdam Rheumatology and Immunology Center VU University Medical CenterAmsterdam 1007 MBThe Netherlands

P-glycoprotein(ABCB1),multidrug resistance protein-1(ABCC1)and breast cancer resistance protein(ABCG2)belong to the ATP-binding cassette(ABC)superfamily of proteins that play an important physiological role in protection of the body from toxic xenobiotics and endogenous *** this,these transporters determine the toxicity profile of many drugs,and confer multidrug resistance(MDR)in cancer cells associated with a poor treatment outcome of cancer *** has long been hypothesized that inhibition of ABC drug efflux transporters will increase drug accumulation and thereby overcome MDR,but until now no approved inhibitor of these transporters is available in the *** this review we present molecular strategies to overcome this type of drug resistance and discuss for each of these strategies their promising value or indicate underlying reasons for their limited success.

关键词： Breast cancer resistance protein ATP-binding cassette transporters multidrug resistance multidrug resistance protein

Resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer

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Cancer Drug Resistance 2018年第4期1卷 230-249页

作者： Nele Van Der Steen Elisa Giovannetti Daniela Carbone Alessandro Leonetti Christian D.Rolfo godefridus j.peters Department of Medical Oncology VU University Medical CenterAmsterdam 1081 HVthe Netherlands Department of Pathology Antwerp University HospitalAntwerp 2650Belgium Center for Oncological Research University of AntwerpAntwerp 2610Belgium Cancer Pharmacology Lab AIRC Start-Up UnitUniversity of PisaPisa 56124Italy Medical Oncology Unit University Hospital of ParmaParma 43126Italy University of Maryland Greenebaum Comprehensive Cancer Center Baltimore21220 MDUSA

Aberrant activation of the epidermal growth factor receptor(EGFR)is a driving force for cancer growth in a subgroup of non-small cell lung cancer *** patients can be identified by the presence of activating EGFR *** three generations of EGFR-tyrosine kinase inhibitors(TKIs)have been approved by the Food and Drug Administration and European Medicine *** paper reviews the structure of EGFR and the downstream signaling pathways of EGFR and describes the mechanisms of intrinsic and acquired resistance against *** mechanisms include secondary or tertiary mutations in EGFR,the activation of bypassing signaling pathways or a histological transformation to small cell lung ***,drug efflux transporters will affect the cellular accumulation of EGFR-TKIs and penetration of the first generation of EGFR-TKI into the *** sequestration of some EGFR-TKIs may also prevent the drugs to reach their *** conclusion,resistance to EGFR-TKIs is multifactorial,including primary and acquired mutations in the EGFR gene,activation of bypassing pathways and limited uptake of drugs in the cells or target *** pharmacological studies are needed in order to develop new specific compounds targeted to overcome new resistance mechanisms in order to enable a personalized treatment approach.

关键词： Epidermal growth factor receptor non-small cell lung cancer resistance EGFR-tyrosine kinase inhibitors erlotinib gefitinib afatinib osimertinib rociletinib

Statins markedly potentiate aminopeptidase inhibitor activity against(drug-resistant)human acute myeloid leukemia cells

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Cancer Drug Resistance 2023年第3期6卷 430-446页

作者： Gerrit jansen Marjon Al Yehuda G.Assaraf Sarah Kammerer johan van Meerloo Gert j.Ossenkoppele jacqueline Cloos godefridus j.peters Department of Rheumatology and Clinical Immunology Amsterdam Rheumatology and immunology CenterAmsterdam University Medical Centerlocation VUmcAmsterdam 1081 HVThe Netherlands The Fred Wyszkowsky Cancer Research Laboratory Faculty of BiologyThe Technion-Israel Institute of TechnologyHaifa 3200003Israel Department of Medical Oncology Amsterdam University Medical Centerlocation VUmcAmsterdam 1081 HVThe Netherlands Institute of Biotechnology Molecular Cell BiologyBrandenburg University of Technology Cottbus-SenftenbergSenftenberg 01968Germany Department of Hematology Amsterdam University Medical Centerlocation VUmcAmsterdam 1081 HVThe Netherlands Department of Biochemistry Medical University of GdanskGdansk 80-210Poland

Aim: This study aimed to decipher the molecular mechanism underlying the synergistic effect of inhibitors of the mevalonate-cholesterol pathway (i.e., statins) and aminopeptidase inhibitors (APis) on APi-sensitive and -resistant acute myeloid leukemia (AML) ***: U937 cells and their sublines with low and high levels of acquired resistance to (6S)-[(R)-2-((S)-Hydroxy-hydroxycarbamoyl-methoxy-methyl)-4-methyl-pentanoylamino]-3,3 dimethyl-butyric acid cyclopentyl ester (CHR2863), an APi prodrug, served as main AML cell line models. Drug combination effects were assessed with CHR2863 and in vitro non-toxic concentrations of various statins upon cell growth inhibition, cell cycle effects, and apoptosis induction. Mechanistic studies involved analysis of Rheb prenylation required for mTOR ***: A strong synergy of CHR2863 with the statins simvastatin, fluvastatin, lovastatin, and pravastatin was demonstrated in U937 cells and two CHR2863-resistant sublines. This potent synergy between simvastatin and CHR2863 was also observed with a series of other human AML cell lines (e.g., THP1, MV4-11, and KG1), but not with acute lymphocytic leukemia or multiple solid tumor cell lines. This synergistic activity was: (i) specific for APis (e.g., CHR2863 and Bestatin), rather than for other cytotoxic agents;and (ii) corroborated by enhanced induction of apoptosis and cell cycle arrest which increased the sub-G1 fraction. Consistently, statin potentiation of CHR2863 activity was abrogated by co-administration of mevalonate and/or farnesyl pyrophosphate, suggesting the involvement of protein prenylation;this was experimentally confirmed by impaired Rheb prenylation by ***: These novel findings suggest that the combined inhibitory effect of impaired Rheb prenylation and CHR2863-dependent mTOR inhibition instigates a potent synergistic inhibition of statins and APis on human AML cells.

关键词： Aminopeptidase statins mevalonate pathway carboxyl esterase Rheb mTOR

SF3B1 modulators affect key genes in metastasis and drug influx: a new approach to fight pancreatic cancer chemoresistance

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Cancer Drug Resistance 2021年第4期4卷 904-922页

作者： Ornella Randazzo Stella M.Cascioferro Camilla Pecoraro Widad Ait Iddouch Amir Avan Barbara Parrino Daniela Carbone Ugo Perricone godefridus j.peters Patrizia Diana Elisa Giovannetti Department of Medical Oncology Cancer Center AmsterdamAmsterdam UMCVU University Medical CenterAmsterdam 1081 HVThe Netherlands Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche(STEBICEF) Universitàdegli Studi di PalermoPalermo 90133Italy Metabolic Syndrome Research Center Mashhad University of Medical SciencesMashhad 91886-17871Iran Cancer Research Center Mashhad University of Medical SciencesMashhad 91886-17871Iran Student Research Committee School of MedicineMashhad University of Medical SciencesMashhad 91886-17871Iran Drug Discovery Unit Fondazione Ri.MEDPalermo 90128Italy Department of Biochemistry Medical University of GdanskGdansk 80-210Poland Cancer Pharmacology Lab AIRC Start Up UnitFondazione Pisana per la ScienzaPisa 56124Italy.

Aim:Because mutations of splicing factor 3B subunit-1(SF3B1)have been identified in 4%of pancreatic ductal adenocarcinoma(PDAC)patients,we investigated the activity of new potential inhibitors of SF3B1 in combination with gemcitabine,one of the standard drugs,in PDAC cell ***:One imidazo[2,1-b][1,3,4]thiadiazole derivative(IS1)and three indole derivatives(IS2,IS3 and IS4),selected by virtual screening from an in-house library,were evaluated by the sulforhodamine-B and wound healing assay for their cytotoxic and antimigratory activity in the PDAC cells SUIT-2,Hs766t and Panc05.04,the latter harbouring the SF3B1 *** effects on the splicing pattern of proto-oncogene recepteur d’origine nantais(RON)and the gemcitabine transporter human equilibrative nucleoside transporter-1(hENT1)were assessed by PCR,while the ability to reduce tumour volume was tested in spheroids of primary PDAC ***:The potential SF3B1 modulators inhibited PDAC cell proliferation and prompted induction of cell *** compounds showed an interesting anti-migratory ability,associated with splicing RON/ΔRON shift in SUIT-2 cells after 24 h ***,IS1 and IS4 potentiated the sensitivity to gemcitabine in both conventional 2D monolayer and 3D spheroid cultures,and these results might be explained by the statistically significant increase in hENT1 expression(P<0.05 *** control cells),potentially reversing PDAC ***:These results support further studies on new SF3B1 inhibitors and the role of RON/hENT1 modulation to develop effective drug combinations against PDAC.

关键词： Pancreatic ductal adenocarcinoma gemcitabine indole derivatives anti-proliferative activity anti-migratory activity SF3B1 RON hENT1

Gemcitabine followed by radiotherapy in treatment of newly diagnosed high-grade gliomas

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journal of Cancer Metastasis and Treatment 2016年第1期2卷 188-194页

作者： Maha El-Naggar Mervat Omar Ahmed Elgeriany godefridus j.peters Amina Mostafa Samir Shehata Department of Medical oncology Assiut University HospitalAssiut 71515Egypt Department of Neurosurgery Assiut University HospitalAssiut 71515Egypt Department of Medical Oncology VU University Medical Center1081 HV Amsterdamthe Netherlands

Aim:High-grade glioblastoma multiforme(GBM)has a poor median overall survival(OS).The standard treatment after surgery is temozolomide and radiotherapy(RTH).Patients with unmethylated methylguanine-methyltransferase promoter(MGMT)have no or little benefit from temozolomide and are eligible for alternative *** is a good *** aimed to evaluate the combination of gemcitabine with RTH in newly diagnosed ***:The study was a prospective phase II *** patients were required to have histologically proven anaplastic astrocytoma or *** underwent biopsies or subtotal *** treatment consisted of fixed-dose rate gemcitabine 175 mg/m^(2) weekly followed after 24 h by standard cranial RTH for 6 *** response was evaluated by Macdonald *** case of progression,patients received temozolomide(200 mg/m^(2)/5 days every 28 days).Results:T hirty patients w ith a median age of 52 years(30-69),73%/27%m ale/female,t he Eastern Cooperative Oncology Group performance status 1(range 0-2)were *** patients had a partial-response(17%)and 13 stable-disease(43%).Median time to progression was 7.88 months(95%CI 6.1-9.69)and OS was 11.77 months(95%CI 9.97-13.56).The treatment was well tolerated with grade-3 neutropenia in 3,grade-3 anemia in 2 and impaired liver enzymes in 1 ***:Gemcitabine followed by radiotherapy is active and promising regimen in newly diagnosed *** uptake is easy,with a long local retention of active metabolites,precluding systemic side effects of *** a phase III study this treatment should be evaluated in patients with unmethylated MGMT promoter who will not benefit from temozolomide.

关键词： Gemcitabine radiation glioblastoma multiforma temozolomide

Dynamic evolution of terpenoid biosynthesis in the Lamiaceae

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Molecular Plant 2023年第6期16卷 963-965页

作者： Zhibiao Wang Reuben j.peters School of Life Sciences Beijing University of Chinese MedicineBeijing 100029China Roy j.Carver Department of Biochemistry Biophysics&Molecular Biologylowa State UniversityAmesIA 50011USA

With the increasing accessibility of whole-genome sequencing it has become standard practice to apply such an approach to investigation of plants with important and/or interesting natural *** part,this reflects recognition that plants have occasionally rearranged or shuffled their genes to generate biosynthetic gene clusters(BGCs)for certain natural products(Smit and Lichman,2022;Zhan et al.,2022).

关键词： products evolution

Double-barreled defense: dual ent-miltiradiene synthases in most rice cultivars

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aBIOTECH 2024年第3期5卷 375-380页

作者： Yiling Feng Tristan Weers Reuben j.peters Roy j.Carver Department of Biochemistry Biophysics and Molecular BiologyIowa State UniversityAmesIA 50011USA

Rice(Oryza sativa)produces numerous diterpenoid phytoalexins that are important in defense against ***,despite extensive previous investigations,a major group of such phytoalexins,the abietoryzins,were only recently *** aromatic abietanes are presumably derived from ent-miltiradiene,but such biosynthetic capacity has not yet been reported in *** wild rice has been reported to contain such an enzyme,specifically ent-kaurene synthase-like 10(KSL10),the only characterized ortholog from ***(OsKSL10),specifically from the well-studied cultivar(cv.)Nipponbare,instead has been shown to make ent-sandaracopimaradiene,precursor to the ***,in many other cultivars,OsKSL10 is accompanied by a tandem duplicate,termed here *** characterization of OsKLS14 from *** demonstrates that this produces the expected abietoryzin precursor ***,phylogenetic analysis of OsKSL10 across the rice pan-genome reveals that from *** is an outlier,whereas the alleles from most other cultivars group with those from wild rice,suggesting that these also might produce ***,OsKSL10 from *** exhibits such activity as well,consistent with its production of abietoryzins but not *** consistent with these results is the lack of abietoryzin production by *** their equivalent product outcome might suggest redundancy,OsKSL10 and OsKSL14 were observed to exhibit distinct expression patterns,indicating such differences may underlie retention of these duplicated ***,the results reported here clarify abietoryzin biosynthesis and provide insight into the evolution of rice diterpenoid phytoalexins.

关键词： Phytoalexins Diterpenoids Diterpene synthases Tandem gene duplication Neofunctionalization