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

scholarly journals pH-activated, mitochondria-targeted, and redox-responsive delivery of paclitaxel nanomicelles to overcome drug resistance and suppress metastasis in lung cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
He Wang ◽  
Wenwen Shi ◽  
Danning Zeng ◽  
Qiudi Huang ◽  
Jiacui Xie ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Disulfide Bonds ◽  
Cancer Metastasis ◽  
Mitochondrial Outer Membrane ◽  
Drug Resistant ◽  
Redox Responsive ◽  
Dimethylmaleic Anhydride ◽  
Extended Circulation ◽  
Mitochondria Targeting

Abstract Background Mitochondria play a role in the occurrence, development, drug resistance, metastasis, and other functions of cancer and thus are a drug target. An acid-activated mitochondria-targeting drug nanocarrier with redox-responsive function was constructed in the present study. However, whether this vector can precisely delivery paclitaxel (PTX) to enhance therapeutic efficacy in drug-resistant lung cancer is unknown. Results Acid-cleavable dimethylmaleic anhydride (DA) was used to modify pluronic P85-conjugated mitochondria-targeting triphenylphosphonium (TPP) using disulfide bonds as intermediate linkers (DA-P85-SS-TPP and DA-P-SS-T). The constructed nanocarriers demonstrated enhanced cellular uptake and selective mitochondrial targeting at extracellular pH characteristic for a tumor (6.5) and were characterized by extended circulation in the blood. TPP promoted the targeting of the DA-P-SS-T/PTX nanomicelles to the mitochondrial outer membrane to decrease the membrane potential and ATP level, resulting in inhibition of P-glycoprotein and suppression of drug resistance and cancer metastasis. PTX was also rapidly released in the presence of high glutathione (GSH) levels and directly diffused into the mitochondria, resulting in apoptosis of drug-resistant lung cancer cells. Conclusions These promising results indicated that acid-activated mitochondria-targeting and redox-responsive nanomicelles potentially represent a significant advancement in cancer treatment. Graphic Abstarct

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.

scholarly journals Selection for Drug Resistance Results in Resistance to Fas-Mediated Apoptosis

Blood ◽  
1997 ◽  
Vol 89 (6) ◽  
pp. 1854-1861 ◽  
Author(s):  
Terry H. Landowski ◽  
Mary C. Gleason-Guzman ◽  
William S. Dalton
Keyword(s):  
Drug Resistance ◽  
Cell Lines ◽  
Antigen Expression ◽  
Lymphoid Cells ◽  
Dependent Manner ◽  
Chemotherapeutic Drugs ◽  
Mechanisms Of Resistance ◽  
Fas Antigen ◽  
Selection For ◽  
Dose Dependent

Abstract Recent evidence has supported the hypothesis that chemotherapeutic drugs and radiation induce an apoptotic pathway that requires the active participation of the cell. One pathway of apoptosis in malignant lymphoid cells is mediated by the Fas antigen. We studied the human myeloma (8226) and T-cell leukemia (CEM) cell lines selected for resistance to the anthracenes, doxorubicin or mitoxantrone, by continuous culture in the presence of either agent. We found that these drug-resistant cell lines were also resistant to Fas-mediated apoptosis in a dose-dependent manner. The degree of resistance to Fas-mediated apoptosis correlated directly with the level of resistance to chemotherapeutic drugs. These observations indicate that, as cancer cell lines develop mechanisms of drug resistance, they may also develop mechanisms of resistance to physiologic signals of apoptosis. Two mechanisms of resistance to Fas-mediated apoptosis were observed in these cell lines. One mechanism was associated with a dose-dependent reduction in the surface expression of Fas antigen. Analysis of RNA by reverse transcriptase-polymerase chain reaction assays showed that the reduction of Fas antigen expression occurred at the level of transcription. A second mechanism of drug resistance showed no decrease of Fas antigen expression; however, the apoptotic response was diminished. In this situation, removal of the chemotherapeutic agent resulted in a partial reversion to chemosensitivity and re-expression of the Fas antigen, but these cell lines did not regain the ability to undergo apoptosis in response to cross-linking by anti-Fas antibody. These findings support the hypothesis that apoptosis mediated by both chemotherapeutic agents and physiologic stimuli may share a common downstream effector. The demonstration that selection for drug resistance in hematopoietic cell lines results in a simultaneous resistance to Fas-mediated apoptosis may have clinical implications in the development of strategies for the treatment of resistant disease. Further analysis of the molecular mechanisms of Fas expression and function will facilitate the design of biological response modifying agents for the treatment of malignancy.

scholarly journals Conjugation of Doxorubicin to siRNA Through Disulfide-based Self-immolative Linkers

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2714 ◽  
Author(s):  
Florian Gauthier ◽  
Jean-Rémi Bertrand ◽  
Jean-Jacques Vasseur ◽  
Christelle Dupouy ◽  
Françoise Debart
Keyword(s):  
Disulfide Bonds ◽  
Chemotherapeutic Drugs ◽  
Exchange Reactions ◽  
Disulfide Exchange ◽  
Physiological Conditions ◽  
Drug Conjugates ◽  
Reducing Conditions ◽  
Redox Responsive ◽  
Covalent Interactions ◽  
Premature Release

Co-delivery systems of siRNA and chemotherapeutic drugs have been developed as an attractive strategy to optimize the efficacy of chemotherapy towards cancer cells with multidrug resistance. In these typical systems, siRNAs are usually associated to drugs within a carrier but without covalent interactions with the risk of a premature release and degradation of the drugs inside the cells. To address this issue, we propose a covalent approach to co-deliver a siRNA-drug conjugate with a redox-responsive self-immolative linker prone to intracellular glutathione-mediated disulfide cleavage. Herein, we report the use of two disulfide bonds connected by a pentane spacer or a p-xylene spacer as self-immolative linker between the primary amine of the anticancer drug doxorubicin (Dox) and the 2′-position of one or two ribonucleotides in RNA. Five Dox-RNA conjugates were successfully synthesized using two successive thiol-disulfide exchange reactions. The Dox-RNA conjugates were annealed with their complementary strands and the duplexes were shown to form an A-helix sufficiently stable under physiological conditions. The enzymatic stability of Dox-siRNAs in human serum was enhanced compared to the unmodified siRNA, especially when two Dox are attached to siRNA. The release of native Dox and RNA from the bioconjugate was demonstrated under reducing conditions suggesting efficient linker disintegration. These results demonstrate the feasibility of making siRNA-drug conjugates via disulfide-based self-immolative linkers for potential therapeutic applications.

Co-delivery of chemotherapeutic drugs with vitamin E TPGS by porous PLGA nanoparticles for enhanced chemotherapy against multi-drug resistance

Biomaterials ◽  
2014 ◽  
Vol 35 (7) ◽  
pp. 2391-2400 ◽  
Author(s):  
Huijun Zhu ◽  
Hongbo Chen ◽  
Xiaowei Zeng ◽  
Zhongyuan Wang ◽  
Xudong Zhang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Vitamin E ◽  
Plga Nanoparticles ◽  
Multi Drug Resistance ◽  
Chemotherapeutic Drugs ◽  
Vitamin E Tpgs

Molecular basis of bortezomib resistance: proteasome subunit β5 (PSMB5) gene mutation and overexpression of PSMB5 protein

Blood ◽  
2008 ◽  
Vol 112 (6) ◽  
pp. 2489-2499 ◽  
Author(s):  
Ruud Oerlemans ◽  
Niels E. Franke ◽  
Yehuda G. Assaraf ◽  
Jacqueline Cloos ◽  
Ina van Zantwijk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Drug Resistance ◽  
Molecular Basis ◽  
Proteasome Inhibitor ◽  
Acquired Resistance ◽  
Binding Pocket ◽  
Cross Resistance ◽  
Chemotherapeutic Drugs ◽  
Proteasome Subunits

AbstractThe proteasome inhibitor bortezomib is a novel anticancer drug that has shown promise in the treatment of refractory multiple myeloma. However, its clinical efficacy has been hampered by the emergence of drug-resistance phenomena, the molecular basis of which remains elusive. Toward this end, we here developed high levels (45- to 129-fold) of acquired resistance to bortezomib in human myelomonocytic THP1 cells by exposure to stepwise increasing (2.5-200 nM) concentrations of bortezomib. Study of the molecular mechanism of bortezomib resistance in these cells revealed (1) an Ala49Thr mutation residing in a highly conserved bortezomib-binding pocket in the proteasome β5-subunit (PSMB5) protein, (2) a dramatic overexpression (up to 60-fold) of PSMB5 protein but not of other proteasome subunits including PSMB6, PSMB7, and PSMA7, (3) high levels of cross-resistance to β5 subunit-targeted cytotoxic peptides 4A6, MG132, MG262, and ALLN, but not to a broad spectrum of chemotherapeutic drugs, (4) no marked changes in chymotrypsin-like proteasome activity, and (5) restoration of bortezomib sensitivity in bortezomib-resistant cells by siRNA-mediated silencing of PSMB5 gene expression. Collectively, these findings establish a novel mechanism of bortezomib resistance associated with the selective overexpression of a mutant PSMB5 protein.

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