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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) cells.Methods: 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 activation.Results: 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 simvastatin.Conclusion: 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

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 immunofluorescence.Results:Colo320 and Colo320TP1 cells had comparable levels of sensitivity to the mTOR inhibitor rapamycin.Thymidine treatment led to 13-and 50-fold resistance to rapamycin in Colo320 and Colo320TP1 cells,respectively.In 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 protection.Thymidine increased p70/S6k-phosphorylation(downstream of mTOR)in Colo320TP1,but it was not affected in Colo320.As 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 TPI.In addition,the autophagy inhibitor 3-methyl-adenine completely inhibited autophagy and its protection.Conclusion: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

Cancer drug resistance: a new perspective

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Cancer Drug Resistance 2018年第1期1卷 1-5页

作者： godefridus j.peters Laboratory Medical Oncology VU University Medical CenterCancer Center AmsterdamAmsterdam 1007 MBThe Netherlands

INTRODUCTION Cancer drug resistance has been and unfortunately still is a major problem in cancer therapy.Almost any therapy(except surgery)that is being used in the treatment of cancer can result in resistance.Unfortunately there is a large group of patients that will either not respond to the applied therapy(intrinsic resistance)or will become resistant during therapy(acquired resistance).Sometimes patients can become resistant to one specific drug and remain sensitive to other drugs(one-drug resistance);another group of patients may become resistant to one drug and will be resistant to other unrelated drugs as well(multiple drug resistance,MDR).

关键词： drugs Cancer drug

Role of Akt signaling in resistance to DNA-targeted therapy

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世界临床肿瘤学杂志：英文版 2016年第5期7卷 352-369页

作者： Abolfazl Avan Ravi Narayan Elisa Giovannetti godefridus j peters Department of Medical Oncology VU University Medical Center Department of Radiation Oncology VU University Medical Center

The Akt signal transduction pathway controls most hallmarks of cancer. Activation of the Akt cascade promotes a malignant phenotype and is also widely implicated in drug resistance. Therefore, the modulation of Akt activity is regarded as an attractive strategy to enhance the efficacy of cancer therapy and irradiation. This pathway consists of phosphatidylinositol 3 kinase(PI3K), mammalian target of rapamycin, and the transforming serine-threonine kinase Akt protein isoforms, also known as protein kinase B. DNA-targeted agents, such as platinum agents, taxanes, and antimetabolites, as well as radiation have had a significant impact on cancer treatment by affecting DNA replication, which is aberrantly activated in malignancies. However, the caveat is that they may also trigger the activation of repairing mechanisms, such as upstream and downstream cascade of Akt survival pathway. Thus, each target can theoretically be inhibited in view of improving the potency of conventional treatment. Akt inhibitors, e.g., MK-2206 and perifosine, or PI3K modulators, e.g., LY294002 and Wortmannin, have shown some promising results in favor of sensitizing the cancer cells to the therapy in vitro and in vivo, which have provided the rationale for incorporation of these novel agents into multimodality treatment of different malignancies. Nevertheless, despite the acceptable safety profile of some of these agents in the clinical studies, with regard to the efficacy, the results are still too preliminary. Hence, we need to wait for the upcoming data from the ongoing trials before utilizing them into the standard care of cancer patients.

关键词： Phosphatidylinositol 3 kinase/Akt Platinum Taxane Antimetabolite Radiation

Efficacy of thioguanine treatment in inflammatory bowel disease: A systematic review

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World journal of Gastroenterology 2016年第40期22卷 9012-9021页

作者： Berrie Meijer Chris jj Mulder godefridus j peters Adriaan A van Bodegraven Nanne KH de Boer Department of Gastroenterology and Hepatology VU University Medical Center Department of Medical Oncology VU University Medical Center Department of Gastroenterology Geriatrics Internal and Intensive Care Medicine (Co-MIK) Zuyderland Medical Center

AIM To critically assess the available literature regarding the efficacy of thioguanine treatment in inflammatory bowel disease(IBD) patients, irrespective of the(hepato-) toxicity profile.METHODS A systematic literature search of the MEDLINE database using Pub Med was performed using the keywords "thioguanine", "6-TG", "thioguanine", "inflammatory bowel disease", "IBD", "Crohn's disease", "Ulcerative colitis" and "effectiveness" in order to identify relevant articles published in English starting from 2000. Reference lists of the included articles were crosschecked for missing articles. Reviewed manuscripts concerning the effectiveness of thioguanine treatment in IBD were reviewed by the authors and the data were extracted. Data were subsequently analyzed with descriptive statistics. Due to the lack of standardized outcomes, a formal meta-analysis was not performed.RESULTS A total of 11 applicable studies were found that involved the effectiveness of thioguanine therapy in IBD. Eight studies were conducted in a prospectivemanner, in the remaining three studies, data was collected retrospectively. In total, 353 IBD-patients(225 patients with Crohn's disease, 119 with ulcerative colitis and nine with unclassified IBD) with prior azathioprine/mercaptopurine resistance and/or intolerance(n = 321) or de novo thioguanine administration(n = 32) were included for analysis, of which 228(65%) had clinical improvement on thioguanine therapy, based on standard IBD questionnaires, biochemical parameters or global physician assessments. Short-term results were based on 268 treatment years(median follow-up 9 mo, range 3-22 mo) with a median daily dose of 20 mg(range 10-80 mg). Discontinuation, mostly due to adverse events, was reported in 72 patients(20%). CONCLUSION The efficacy of thioguanine therapy in IBD patients intolerant to conventional thiopurine therapy is observed in 65%, with short term adverse events in 20% of patients.

关键词： Thiopurines Thioguanine 煽动性的肠疾病 Crohn’ s 疾病 Ulcerative 大肠炎

Tyrosine kinase inhibitors:Multi-targeted or single-targeted?

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World journal of Clinical Oncology 2011年第2期2卷 80-93页

作者： Fleur Broekman Elisa Giovannetti godefridus j peters Department of Medical Oncology VU University Medical Center1007 MB AmsterdamThe Netherlands

Since in most tumors multiple signaling pathways are involved,many of the inhibitors in clinical development are designed to affect a wide range of targeted kinases.The most important tyrosine kinase families in the development of tyrosine kinase inhibitors are the ABL,SCR,platelet derived growth factor,vascular endothelial growth factor receptor and epidermal growth factor receptor families.Both multi-kinase inhibitors and singlekinase inhibitors have advantages and disadvantages,which are related to potential resistance mechanisms,pharmacokinetics,selectivity and tumor environment.In different malignancies various tyrosine kinases are mutated or overexpressed and several resistance mechanisms exist.Pharmacokinetics is influenced by interindividual differences and differs for two single targeted inhibitors or between patients treated by the same tyrosine kinase inhibitor.Different tyrosine kinase inhibitors have various mechanisms to achieve selectivity,while differences in gene expression exist between tumor and stromal cells.Considering these aspects,one type of inhibitor can generally not be preferred above the other,but will depend on the specific genetic constitution of the patient and the tumor,allowing personalized therapy.The most effective way of cancer treatment by using tyrosine kinase inhibitors is to consider each patient/tumor individually and to determine the strategy that specifically targets the consequences of altered(epi)genetics of the tumor.This strategy might result in treatment by a single multi kinase inhibitor for one patient,but in treatment by a couple of single kinase inhibitors for other patients.

关键词： Tyrosine kinase inhibitors Targeted therapy Epidermal growth factor receptor Vascular endothelial growth factor receptor Platelet derived growth factor Breakpoint cluster region-Abelson murine leukemia oncogene homolog 1 janus kinase

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 metabolites.Beyond 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 patients.It 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 clinic.In 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

FOLFIRINOX and translational studies: Towards personalized therapy in pancreatic cancer

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World journal of Gastroenterology 2016年第31期22卷 6987-7005页

作者： Chiara Caparello Laura L Meijer Ingrid Garajova Alfredo Falcone Tessa Y Le Large Niccola Funel Geert Kazemier godefridus j peters Enrico Vasile Elisa Giovannetti University Hospital of Pisa 56124 Pisa Italy Department of Medical Oncology VU University Medical Center 1081 HV Amsterdam The Netherlands Department of Surgery VU University Medical Center 1081 HV Amsterdam The Netherlands Department of Experimental Diagnostic and Speciality Medicine University of Bologna Sant'Orsola-Malpighi Hospital Via Massarenti 9 40138 Bologna Italy Cancer Pharmacology Lab AIRC Start-Up Unit University of Pisa 56124 Pisa Italy CNR-Nano Institute of Nanoscience and Nanotechnology University of Pisa 56124 Pisa Italy

Pancreatic cancer is an extremely aggressive disease; although progress has been made in the last few years, the prognosis of these patients remains dismal. FOLFIRINOX is now considered a standard treatment in first-line setting, since it demonstrated an improved overall and progression-free survival vs gemcitabine alone. However, the enthusiasm over the benefit of this three-drug regimen is tempered by the associated increased toxicity profile, and many efforts have been made to improve the feasibility of this schedule. After a more recent phase Ⅲ trial showing an improved outcome over gemcitabine, the combination of gemcitabine/nab-paclitaxel emerged as another standard first-line treatment. However, this treatment is also associated with more side effects. In addition, despite initial promising data on the predictive role of SPARClevels, recent studies showed that these levels are not associated with nab-paclitaxel efficacy. The choice to use this treatment over FOLFIRINOX is therefore a topic of debate, also because no validated biomarkers to guide FOLFIRINOX treatment are available. In the era of actionable mutations and target agents it would be desirable to identify molecular factors or biomarkers to predict response to therapy in order to maximize the efficacy of treatment and avoid useless toxic effects for non-responding patients. However, until today the milestone of treatment for pancreatic cancer remains chemotherapy combinations, without predictive or monitoring tools existing to optimize therapy. This review analyzes the state-of-the-art treatments, promises and limitations of targeted therapies, ongoing trials and future perspectives, including potential role of microR NAs as predictive biomarkers.

关键词： FOLFIRINOX Personalized therapy New treatments MicroR NA Pancreatic cancer

Better to be alone than in bad company:The antagonistic effect of cisplatin and crizotinib combination therapy in non-small cell lung cancer

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World journal of Clinical Oncology 2016年第6期7卷 425-432页

作者： Nele Van Der Steen Christophe Deben Vanessa Deschoolmeester An Wouters Filip Lardon Christian Rolfo Paul Germonpré Elisa Giovannetti godefridus j peters Patrick Pauwels Center for Oncological Research University of Antwerp Department of Pathology Antwerp University Hospital Department of Medical Oncology VU University Medical Center Department of Oncology Antwerp University Hospital Department of Pneumology Cancer Pharmacology Lab AIRC Start-Up UnitUniversity of Pisa

AIM To investigate the potential benefit of combining the cMET inhibitor crizotinib and cisplatin we performed in vitro combination studies.METHODS We tested three different treatment schemes in four non-small cell lung cancer(NSCLC) cell lines with a different cMET/epidermal growth factor receptor genetic background by means of the sulforhodamine B assay and performed analysis with Calcusyn.RESULTS All treatment schemes showed an antagonistic effect in all cell lines,independent of the cMET status.Despite their different genetic backgrounds,all cell lines(EBC-1,HCC827,H1975 and LUDLU-1) showed antagonistic combination indexes ranging from 1.3-2.7.These results were independent of the treatment schedule.CONCLUSION These results discourage further efforts to combine cMET inhibition with cisplatin chemotherapy in NSCLC.

关键词： Non-small cell lung cancer Combination therapy Cisplatin Crizotinib cMET