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| 1 | How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?显示文摘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. | Adrian C.Jaramillo Farah Al Saig Jacqueline Cloos Gerrit Jansen Godefridus J.Peters | 2018 | Cancer Drug Resistance2018，1，1： | 3 |
| 2 | Cancer drug resistance: a new perspective显示文摘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). | Godefridus J.Peters | 2018 | Cancer Drug Resistance2018，1，1： | 2 |
| 3 | Protective autophagy by thymidine causes resistance to rapamycin in colorectal cancer cells in vitro显示文摘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. | I.V.Bijnsdorp Godefridus J.Peters | 2021 | Cancer Drug Resistance2021，4，3： | 2 |
| 4 | Molecular mechanism underlying the synergistic interaction between trifluorothymidine and the epidermal growth factor receptor inhibitor erlotinib in human colorectal cancer cell lines显示文摘 | Irene V.Bijnsdorp Frank A. E.Kruyt MasakazuFukushima KeesSmid ShantiGokoel Godefridus J.Peters | 2010 | Cancer Science2010，，2： | 1 |
| 5 | Fungal mycobiome-mediated immune response:a non-negligible promoter in pancreatic oncogenesis and chemoresistance显示文摘Pancreatic ductal adenocarcinoma(PDAC)is one of the most lethal cancers in humans due to late diagnosis and poor response to treatments.The 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 progression.Recently,the study of Alam et al.discovered 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-)33.In this article,we reviewed the important findings of this study.Together with our findings,we synthetically discussed the role of the fungal mycobiome in orchestrating the immune response and thereby modulating tumor progression. | Yaling Jiang Valentina Donati Godefridus J.Peters Elisa Giovannetti Dong Mei Deng | 2023 | Cancer Drug Resistance2023，6，2： | 0 |
| 6 | Statins markedly potentiate aminopeptidase inhibitor activity against(drug-resistant)human acute myeloid leukemia cells显示文摘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. | Gerrit Jansen Marjon Al Yehuda G.Assaraf Sarah Kammerer Johan van Meerloo Gert J.Ossenkoppele Jacqueline Cloos Godefridus J.Peters | 2023 | Cancer Drug Resistance2023，6，3： | 0 |
| 7 | Gemcitabine followed by radiotherapy in treatment of newly diagnosed high-grade gliomas显示文摘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 therapies.Gemcitabine is a good radiosensitizer.We aimed to evaluate the combination of gemcitabine with RTH in newly diagnosed GBM.Methods:The study was a prospective phase II study.Eligible patients were required to have histologically proven anaplastic astrocytoma or GBM.Patients underwent biopsies or subtotal resection.The treatment consisted of fixed-dose rate gemcitabine 175 mg/m^(2) weekly followed after 24 h by standard cranial RTH for 6 weeks.Tumor response was evaluated by Macdonald criteria.In 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 enrolled.Five 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 patient.Conclusion:Gemcitabine followed by radiotherapy is active and promising regimen in newly diagnosed GBM.Gemcitabine uptake is easy,with a long local retention of active metabolites,precluding systemic side effects of radiosensitization.In a phase III study this treatment should be evaluated in patients with unmethylated MGMT promoter who will not benefit from temozolomide. | Maha El-Naggar Mervat Omar Ahmed Elgeriany Godefridus J.Peters Amina Mostafa Samir Shehata | 2016 | Journal of Cancer Metastasis and Treatment2016，2，1： | 0 |
| 8 | SF3B1 modulators affect key genes in metastasis and drug influx: a new approach to fight pancreatic cancer chemoresistance显示文摘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 lines.Methods: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 mutations.The 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 cells.Results:The potential SF3B1 modulators inhibited PDAC cell proliferation and prompted induction of cell death.All compounds showed an interesting anti-migratory ability,associated with splicing RON/ΔRON shift in SUIT-2 cells after 24 h exposure.Moreover,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 vs.untreated control cells),potentially reversing PDAC chemoresistance.Conclusion:These results support further studies on new SF3B1 inhibitors and the role of RON/hENT1 modulation to develop effective drug combinations against PDAC. | 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 | 2021 | Cancer Drug Resistance2021，4，4： | 0 |
| 9 | Resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer显示文摘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.These patients can be identified by the presence of activating EGFR mutations.Currently three generations of EGFR-tyrosine kinase inhibitors(TKIs)have been approved by the Food and Drug Administration and European Medicine Agency.This paper reviews the structure of EGFR and the downstream signaling pathways of EGFR and describes the mechanisms of intrinsic and acquired resistance against EGFR-TKIs.These mechanisms include secondary or tertiary mutations in EGFR,the activation of bypassing signaling pathways or a histological transformation to small cell lung cancer.Moreover,drug efflux transporters will affect the cellular accumulation of EGFR-TKIs and penetration of the first generation of EGFR-TKI into the brain.Lysosomal sequestration of some EGFR-TKIs may also prevent the drugs to reach their target.In 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 tissues.More 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. | Nele Van Der Steen Elisa Giovannetti Daniela Carbone Alessandro Leonetti Christian D.Rolfo Godefridus J.Peters | 2018 | Cancer Drug Resistance2018，1，4： | 0 |
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