The role of copper transporters in the development of resistance to Pt drugs

Mosquitoes’ increasing resistance to insecticides is becoming a major threat for control efforts worldwide. Multiple P450 genes that are up-regulated in permethrin resistant strains of Culex quinquefasciatus have been linked to the development of resistance. In the current study, we characterized the function of six P450 genes, CYP6P14, CYP6BZ2, CYP9J33, CYP9J34, CYP9J40, and CYP9J45, that are overexpressed in the permethrin resistant Culex mosquitoes and showed their capability in metabolism of permethrin. These six P450 genes can convert 3-phenoxybenzoic alcohol (PBCHO) to a less toxic product, 3-phenoxybenzoic acid (PBCOOH), indicating that these P450s play an important role in permethrin degradation pathways. Although we know multiple P450 genes are over-expressed in permethrin resistant Culex mosquitoes, it remains to be seen whether cytochrome P450-reductase (CPR) gene that are co-overexpressed with P450 genes in permethrin resistant mosquitoes do indeed serve as a resistance mechanism. An in-depth investigation of the expression of CPR gene in resistant mosquitoes was conducted in permethrin resistant mosquitoes. The finding of CPR gene overexpression in permethrin resistant mosquitoes suggested the importance of co-overexpression of multiple P450 genes with their obligatory electron donor CPR in the complex detoxification system, boosting the metabolism of permethrin and hence the development of permethrin resistance in Cx. quinquefasciatus.

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Cancer-Associated Fibroblast Functions as a Road-Block in Cancer Therapy

Cancers ◽

10.3390/cancers13205246 ◽

2021 ◽

Vol 13 (20) ◽

pp. 5246

Author(s):

Pradip De ◽

Jennifer Aske ◽

Nandini Dey

Keyword(s):

Cancer Therapy ◽

Solid Tumors ◽

Treatment Resistance ◽

Activation Markers ◽

Cancer Associated Fibroblast ◽

Development Of Resistance ◽

Origin Activation ◽

Crucial Component ◽

Resident Fibroblast

The journey of a normal resident fibroblast belonging to the tumor microenvironment (TME) from being a tumor pacifier to a tumor patron is fascinating. We introduce cancer-associated fibroblast (CAF) as a crucial component of the TME. Activated-CAF partners with tumor cells and all components of TME in an established solid tumor. We briefly overview the origin, activation, markers, and overall functions of CAF with a particular reference to how different functions of CAF in an established tumor are functionally connected to the development of resistance to cancer therapy in solid tumors. We interrogate the role of CAF in mediating resistance to different modes of therapies. Functional diversity of CAF in orchestrating treatment resistance in solid tumors portrays CAF as a common orchestrator of treatment resistance; a roadblock in cancer therapy.

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CCND3 is indispensable for the maintenance of B-cell acute lymphoblastic leukemia

Oncogenesis ◽

10.1038/s41389-021-00377-0 ◽

2022 ◽

Vol 11 (1) ◽

Author(s):

Franz Ketzer ◽

Hend Abdelrasoul ◽

Mona Vogel ◽

Ralf Marienfeld ◽

Markus Müschen ◽

...

Keyword(s):

Cell Cycle Progression ◽

Kinase Activity ◽

Lymphoblastic Leukemia ◽

Mrna Level ◽

Driver Mutations ◽

Development Of Resistance ◽

Apoptotic Effect ◽

Cell Acute Lymphoblastic Leukemia ◽

Activating Transcription Factor

AbstractThe D-type cyclins (CCND1, CCND2, and CCND3) in association with CDK4/6 are known drivers of cell cycle progression. We reported previously that inactivation of FOXO1 confers growth arrest and apoptosis in B-ALL, partially mediated by subsequent depletion of CCND3. Given that previously the canonical MYC target CCND2 has been considered to play the major role in B-ALL proliferation, further investigation of the role of FOXO1 in CCND3 transcription and the role of CCND3 in B-ALL is warranted. In this study, we demonstrated that CCND3 is essential for the proliferation and survival of B-ALL, independent of the mutational background. Respectively, its expression at mRNA level exceeds that of CCND1 and CCND2. Furthermore, we identified FOXO1 as a CCND3-activating transcription factor in B-ALL. By comparing the effects of CCND3 depletion and CDK4/6 inhibition by palbociclib on B-ALL cells harboring different driver mutations, we found that the anti-apoptotic effect of CCND3 is independent of the kinase activity of the CCND3-CDK4/6 complex. Moreover, we found that CCND3 contributes to CDK8 transcription, which in part might explain the anti-apoptotic effect of CCND3. Finally, we found that increased CCND3 expression is associated with the development of resistance to palbociclib. We conclude that CCND3 plays an essential role in the maintenance of B-ALL, regardless of the underlying driver mutation. Moreover, downregulation of CCND3 expression might be superior to inhibition of CDK4/6 kinase activity in terms of B-ALL treatment.

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Exposure of Candida parapsilosis complex to agricultural azoles: An overview of the role of environmental determinants for the development of resistance

The Science of The Total Environment ◽

10.1016/j.scitotenv.2018.09.096 ◽

2019 ◽

Vol 650 ◽

pp. 1231-1238 ◽

Cited By ~ 9

Author(s):

Raimunda Sâmia Nogueira Brilhante ◽

Lucas Pereira de Alencar ◽

Silviane Praciano Bandeira ◽

Jamille Alencar Sales ◽

Antônio José de Jesus Evangelista ◽

...

Keyword(s):

Candida Parapsilosis ◽

Environmental Determinants ◽

Development Of Resistance ◽

Candida Parapsilosis Complex

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A Review on DNA Repair Inhibition by PARP Inhibitors in Cancer Therapy

Folia Medica ◽

10.1515/folmed-2017-0067 ◽

2018 ◽

Vol 60 (1) ◽

pp. 39-47 ◽

Cited By ~ 8

Author(s):

Ashish P. Shah ◽

Chhagan N. Patel ◽

Dipen K. Sureja ◽

Kirtan P. Sanghavi

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Cancer Therapy ◽

Repair Process ◽

Parp Inhibitors ◽

Brca Mutations ◽

Development Of Resistance ◽

Damage Repair ◽

Future Therapy

AbstractThe DNA repair process protects the cells from DNA damaging agent by multiple pathways. Majority of the cancer therapy cause DNA damage which leads to apoptosis. The cell has natural ability to repair this damage which ultimately leads to development of resistance of drugs. The key enzymes involved in DNA repair process are poly(ADP-ribose) (PAR) and poly(ADP-ribose) polymerases (PARP). Tumor cells repair their defective gene via defective homologues recombination (HR) in the presence of enzyme PARP. PARP inhibitors inhibit the enzyme poly(ADP-ribose) polymerases (PARPs) which lead to apoptosis of cancer cells. Current clinical data shows the role of PARP inhibitors is not restricted to BRCA mutations but also effective in HR dysfunctions related tumors. Therefore, investigation in this area could be very helpful for future therapy of cancer. This review gives detail information on the role of PARP in DNA damage repair, the role of PARP inhibitors and chemistry of currently available PARP inhibitors.

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Laws, Liberties, and the Will of the People

10.1093/oso/9780199674886.003.0008 ◽

2021 ◽

pp. 155-177

Author(s):

Sarah Mortimer

Keyword(s):

The Netherlands ◽

Natural Law ◽

Popular Sovereignty ◽

The Political ◽

Dutch Revolt ◽

Development Of Resistance ◽

The People ◽

The Will ◽

Role Of Religion

From the 1560s, tensions between Protestant and Catholics escalated and this was accompanied by a wave of writing on political and religious ideas, especially in France and the Netherlands. There was a renewed interest in the nature and origins of authority within the political sphere, particularly the importance of the ‘people’ and the ways in which their will could be both represented and controlled. This chapter considers some of the key texts of resistance theory written in the 1560s and 1570s, including Francogallia and the Vindiciae, Contra Tyrannos in France, and George Buchanan’s De Jure Regni apud Scotos in Scotland. Discussions of liberty and privileges in the Netherlands during the Dutch Revolt are also considered; here historically based arguments began to be supplemented by appeals to wider principles of morality and natural law. The election of Henry of Valois to the Polish throne provides one example of elective monarchy in practice. This chapter discusses the role of religion and of legal arguments in the development of resistance theories. It also highlights some of the practical and conceptual difficulties in appealing to popular sovereignty, especially in a period of deep confessional divisions, and shows how the authority of magistrates could be understood in different ways.

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Targeting CDC7 sensitizes resistance melanoma cells to BRAFV600E-specific inhibitor by blocking the CDC7/MCM2-7 pathway

Scientific Reports ◽

10.1038/s41598-019-50732-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Shaimaa A. Gad ◽

Hamdy E. A. Ali ◽

Rofaida Gaballa ◽

Rania M. Abdelsalam ◽

Mourad Zerfaoui ◽

...

Keyword(s):

Drug Resistance ◽

Metastatic Melanoma ◽

Clinical Effect ◽

Specific Inhibitor ◽

Melanoma Cells ◽

Development Of Resistance ◽

Dual Targeting ◽

Low Concentrations ◽

Resistant Cells

Abstract Although the utilization of selective BRAFV600E inhibitors is associated with improved overall survival in patients with metastatic melanoma, a growing challenge of drug resistance has emerged. CDC7 has been shown to be overexpressed and associated with poor prognosis in various cancers including melanoma. Thus, we aimed to elucidate the biological role of CDC7 in promoting Vemurafenib resistance and the anticipated benefits of dual targeting of BRAFV600E and CDC7 in melanoma cells. We performed exosomes-associated microRNA profiling and functional assays to determine the role of CDC7 in drug resistance using Vemurafenib-sensitive and resistant melanoma cells. Our results demonstrated that Vemurafenib-resistant cells exhibited a persistent expression of CDC7 in addition to prolonged activity of MCM2 compared to drug-sensitive cells. Reconstitution of miR-3613-3p in resistant cells downregulated CDC7 expression and reduced the number of colonies. Treatment of cells with low concentrations of CDC7 inhibitor TAK-931 sensitized resistant cells to Vemurafenib and reduced the number of cell colonies. Taken together, CDC7 overexpression and downregulation of miR-3613-3p were associated with Vemurafenib resistance in BRAFV600E- bearing melanoma cells. Dual targeting of CDC7 and BRAFV600E reduced the development of resistance against Vemurafenib. Further studies are warranted to investigate the clinical effect of targeting CDC7 in metastatic melanoma.

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