NOVEL FLEXIMER PYRAZOLE-CONTAINING ADENOSINE ANALOGUES: CHEMICAL, ENZYMATIC AND HIGHLY-EFFICIENT BIOTECHNOLOGICAL SYNTHESIS

2021 ◽  
Author(s):  
Anastasia Khandazhinskaya ◽  
Barbara Z. Eletskaya ◽  
Ilja V. Fateev ◽  
Maria I. Kharitonova ◽  
Irina Konstantinova ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Viral Infections ◽  
Nucleoside Analogues ◽  
Chemotherapeutic Drugs ◽  
Adenosine Analogues ◽  
Highly Efficient

Nucleoside analogues have long served as key chemotherapeutic drugs for treatment of viral infections and cancers. Problems associated with the development of drug resistance has led to a search for...

Nucleosides and Nucleoside Analogues as Emerging Antiviral Drugs

2020 ◽  
Vol 17 ◽  
Author(s):  
Mohamed Ibrahim Elzagheid
Keyword(s):  
Significant Role ◽  
Mode Of Action ◽  
Crucial Role ◽  
Viral Infections ◽  
Antiviral Drugs ◽  
Review Article ◽  
Nucleoside Analogues ◽  
The Past ◽  
Nucleoside Drugs

: Nucleosides and their analogues have been in use for many years and have become essential for treating patients with viral infections. Many additional nucleoside drugs have been approved over the past decades. This strongly demonstrates how important these compounds are and the crucial role they play. Given that a significant amount of research and literature has been documented regarding nucleoside analogues, this review article mainly focuses the discussion on nucleosides and nucleoside analogous that have proven to play significant role or be emerging in the treatment of known viral infections. This covers the names, structures, applications, toxicity, and mode of action of relevant nucleoside analogues.

Dominant Role of Raf/MEK/ERK Signaling in Hematopoietic Cell Cycle Progression, Prevention of Apoptosis and Drug Resistance.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1116-1116
Author(s):  
James A. McCubrey ◽  
Steven L. Abrams ◽  
Linda S. Steelman ◽  
Ellis W.T. Wong ◽  
William H. Chappell ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Drug Resistance ◽  
Cell Cycle Progression ◽  
Caspase 3 ◽  
Drug Resistant ◽  
Chemotherapeutic Drugs ◽  
Cycle Progression ◽  
Doxorubicin Treatment ◽  
Mek Inhibitors ◽  
Resistant Cells

Abstract The Ras/Raf/MEK/ERK and PI3K/PTEN/AKT signaling cascades and p53 play critical roles in the transmission of signals from growth factor receptors to regulate gene expression, growth, malignant transformation and drug resistance. We have investigated the roles these two pathways play in cell cycle progression, prevention of apoptosis and drug resistance in cytokine-dependent FL5.12 hematopoietic cells and derivative FL/Akt:ER+Raf-1:AR cells conditionally transformed to grow in response to Akt and Raf activation. The effects of these two pathways on cell cycle progression and sensitivity to chemotherapeutic drugs could be more definitively examined in FL/Akt:ER+Raf-1:AR cells where it is possible to induce either Akt or Raf by themselves or together by the addition of tamoxifen or testosterone. Raf-1 was approximately 8-fold more effective than Akt in maintaining cell cycle progression and preventing apoptosis induced by the chemotherapeutic drugs. However, growth in the presence of chemotherapeutic drugs was enhanced significantly when both Akt and Raf were activated, documenting roles for both Raf and Akt in drug resistance. Drug resistant cells were isolated from both parental and derivative lines in the presence of 10 to 100 nM doxorubicin. Doxorubicin resistant cells were also cross resistant to paclitaxel and daunomycin but not to cisplatin and 5-fluoruracil which are transported by different drug pumps, however, drug resistance did not appear to be mediated by MDR-1/MRP-1 as neither elevated drug pump activity nor higher levels of proteins or mRNAs encoding these proteins were detected, while they were detected in appropriate controls. Drug resistant FL5.12 cells (which lacked any introduced gene) displayed elevated expression of activated ERK, hypersensitivity to Raf and MEK inhibitors and decreased caspase 3 cleavage following doxorubicin treatment. The drug resistance of FL5.12 cells could be further increased 5-fold by introduction of an activated MEK1 gene into the cells and likewise suppressed 8-fold by introduction of a dominant negative (DN) MEK1 gene. Introduction of activated MEK1 also resulted in a further 10-fold decrease in sensitivity to the induction of apoptosis stimulated by doxorubicin treatment as measured by Annexin V/PI binding and Caspase 3 cleavage. These results provide evidence for roles of MEK/ERK in hematopoietic drug resistance. p53 was also involved in drug sensitivity as introduction of DN p53 into FL5.12 cells, which normally express wild-type p53, increased their doxorubicin resistance approximately 3-fold and importantly sensitivity to MEK inhibitors was also determined to be p53-dependent. In summary, our results indicate that the Raf/MEK/ERK pathway is critical in chemotherapy-induced drug resistance and provide rationale for combinations of chemotherapy and Raf/MEK/ERK inhibitors.

Co-Overexpression of YY1 and Gp-170 (MDR1) in Childhood Acute Lymphocytic Leukemia (ALL): Transcription Regulation of Gp-170 by YY1 and Prognostic Significance,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3567-3567
Author(s):  
Gabriela andres-Antonio ◽  
Jesus Rangel-Santiago ◽  
Ana B Tirado-Rodriguez ◽  
Elisa Dorantes-Acosta ◽  
Mario I Vega ◽  
...  
Keyword(s):  
Drug Resistance ◽  
High Risk ◽  
Binding Sites ◽  
Prognostic Significance ◽  
The United States ◽  
Proximal Promoter ◽  
Luciferase Reporter ◽  
Multi Drug Resistance ◽  
Chemotherapeutic Drugs ◽  
Childhood All

Abstract Abstract 3567 Leukemia is the most common cancer among children under the age of 15 years in the United States and many developed countries. In recent years, there has been the emergence of novel therapeutic drugs for this disease. However, the development of drug resistance by the tumor cells remains the most important obstacle in the treatment of leukemia. A widely studied mechanism of tumor resistance to chemotherapeutic drugs is through the expression of the multi-drug resistance (MDR) genes. P-glycoprotein 170 (gp-170) is an MDR1 gene product which serves as an ATP-dependent cell membrane transporter; it facilitates the efflux of xenobiotics (including chemotherapeutic drugs) from the cells to prevent damage for prolonged drug activity, including chemotherapeutics agents. In addition to MDR1, several reports in different cancers have indicated that the transcription factor Yin Yang 1 (YY1) is over-expressed and regulates tumor cell response to chemotherapeutic drugs. Thus, we hypothesized that YY1 may also be over-expressed in ALL and that its expression may be correlated with the expression of gp-170. We also hypothesized that the co-expression of YY1 and gp-170 may be of prognostic significance in high risk ALL patients. These hypotheses were examined with childhood ALL (n= 88) (of median age 8.2 years, range 0.21–16). The expression of YY1 and gp-170 was determined by IHC in tumor tissues and the frequency of YY1 positive cells was determined. For comparison, normal controls were also analyzed (n= 53). The findings demonstrate that were a significant increase in the frequency of positive cells in ALL compared to controls for both YY1 (38% vs. 8%, p= 0.0001) and for gp-170 (42% vs. 12%, p= 0.001). There was a good correlation between the expression of YY1 and gp-170 using Pearson's test, r=0.4, p=0.0001. We then examined if the co-expression of YY1 and gp-170 is also associated with decreased risk. Indeed, patients with low risk (L1) had significantly less frequency of positive cells compared to patients with high risk for both YY1 (40% vs. 30%, p=0.045) and for gp-170 (48% vs. 35%, p=0.0003). The strong correlation betweenYY1 and gp-170 expression suggested that there may be a cross-talk. TESS analysis demonstrated that the gp-170 proximal promoter contains four putative binding sites for the YY-1 protein. The gp-170 protein was cloned and we developed a luciferase reporter assay. Examination of the putative YY1 binding sites that were individually mutated revealed that mutation at the sites -1860 and -270 abolished activity. Mutation at the site -1420 abolished approximately 50% and mutation at -1230 abolished approximately 75%. Further, CHIP analysis demonstrated that YY1 binds directly to the gp-170 gene. Transfection of cells with YY1 siRNA inhibited the efflux of adriamycin from the cells confirming the regulation of gp-170 expression by YY1. Overall, the findings above demonstrate that both gp-170 and YY1 are over-expressed in childhood ALL and further over-expressed in patients with high risk. The findings suggest that YY1 may be a therapeutic target in MDR positive ALL and its inhibition may reverse resistance to chemotherapeutic drugs. Disclosures: No relevant conflicts of interest to declare.

Multiparametric Flow Cytometry of Human Squamous Cell Carcinoma Lines from the Head and Neck

1988 ◽  
Vol 98 (6) ◽  
pp. 552-557 ◽  
Author(s):  
Thomas P.U. Wustrow ◽  
Alexander Raffael ◽  
Günter Valet
Keyword(s):  
Drug Resistance ◽  
Head And Neck ◽  
Cell Lines ◽  
Carcinoma Cell ◽  
Squamous Carcinoma ◽  
Cytotoxic Drug ◽  
Chemotherapeutic Drugs ◽  
Carcinoma Cell Lines ◽  
Squamous Carcinoma Cell

Squamous cell carcinomas of the head and neck consist of heterogeneous cell populations. The purpose of the present study was to Investigate whether established cell lines from human head and neck cancers under chemotherapy behaved similarly to tumors in patients during in vivo treatment. This Is of Interest in terms of improvements of chemotherapeutic protocols and understanding of the mechanisms of cytotoxic drug resistance. Permanent squamous carcinoma cell lines of the larynx (HLaC 78, 79), parotid gland (HPaC 79), tongue (SCC-15, SCC-25), hypopharynx (FaDu), and tumor lines with different histology and origin, as mucoepidermoid cancer cells of the submandibular gland (A 253), Epstein-Barr virus-infected human B cells (BC-1) and mouse fibroblasts (3T3) were Incubated with chemotherapeutic drugs for 1 to 4 days at 37° C. Despite the microscopic similarities to patient carcinomas, cancer cell lines of the head and neck showed different susceptibilities to cell kill mediated by chemotherapeutic drugs, as compared to in vivo therapeutic results with patients. The nonsquamous carcinoma lines demonstrated high chemosensitive responses after incubation with daunorubicin, cyclophosphamide, dactinomycin, vincristine, and aclarubicin. Surprisingly, only low cell killing rates in squamous carcinoma cell lines were observed after incubation with chemotherapeutic agents such as cis-platinum, 5-fluorouracil, methotrexate, or bleomycin, which are most commonly used for head and neck cancers. The results show that cytotoxic drug action on in vitro cultured squamous carcinoma cell lines of the head and neck is not representative for the in vivo responses of patient tumors. The cell lines are, however, of potential value for evaluation of cell biochemical changes associated with cytotoxic drug resistance.

Folate-Targeted Redox-Responsive Polymersomes Loaded with Chemotherapeutic Drugs and Tariquidar to Overcome Drug Resistance

2018 ◽  
Vol 14 (10) ◽  
pp. 1705-1718 ◽  
Author(s):  
Yu Qin ◽  
Zhiming Zhang ◽  
Chenlu Huang ◽  
Fan Fan ◽  
Lanxia Liu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Chemotherapeutic Drugs ◽  
Redox Responsive
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