Baicalin-induced Cytotoxicity and Apoptosis in Multidrug-resistant MC3/5FU Mucoepidermoid Carcinoma Cell Line

2019 ◽  
Vol 16 (12) ◽  
pp. 1339-1347 ◽  
Author(s):  
Xiaofang Xu ◽  
Qihong Li ◽  
Kaitao Yu ◽  
Ghulam Murtaza ◽  
Bin Liu
Keyword(s):  
Flow Cytometry ◽  
Multidrug Resistance ◽  
Nude Mice ◽  
Multidrug Resistant ◽  
Clinical Findings ◽  
Hoechst 33342 ◽  
Protein Levels ◽  
Transmission Electron

Background: Multidrug Resistance (MDR) is a serious hindrance to cancer chemotherapy and profoundly influences the clinical findings. Many Traditional Chinese Medicines (TCM) have been tested with the aim of developing effective resistance modulators or anticancer drugs to overcome the MDR of human cancers. Methods: The anticancer effect of baicalin on multidrug-resistant MC3/5FU (5-fluorouracil) cells was investigated by MTT test and xenografts in nude mice. Cell apoptosis was studied by transmission electron microscopy, Hoechst-33342 staining, DNA fragmentation detection, and flow cytometry. RT-PCR and Rhodamine 123 efflux assay was also used to detect its effect on ABC drug transporter proteins, ABCB1 (P-glycoprotein, P-gp) and ABCC1 (multidrug resistance protein 1, MRP1). Results: The results indicate that there was no significant effect of baicalin on ABC transporters expression or efflux function, although it induced potent growth inhibition in MC3/5FU cells. Flow cytometry, Hoechst 33342 staining and transmission electron microscope revealed that baicalin caused MC3/5FU cell death through the induction of apoptosis. It is demonstrated that baicalininduced apoptosis could be mediated by up-regulation of Bax and caspase-3 protein levels and downregulation of Bcl-2 protein levels. In addition, daily intraperitoneal injection of baicalin (100 and 200 mg/kg) for 2 weeks significantly inhibited the growth of MC3/5FU cells xenografts in nude mice. Conclusion: Our results suggest that baicalin possesses considerable cytotoxic activity in multidrug resistance MC3/5FU cells in vitro and in vivo.

scholarly journals Overcoming multidrug-resistance in vitro and in vivo using the novel P-glycoprotein inhibitor 1416

2012 ◽  
Vol 32 (6) ◽  
pp. 559-566 ◽  
Author(s):  
Yan Xu ◽  
Feng Zhi ◽  
Guangming Xu ◽  
Xiaolei Tang ◽  
Sheng Lu ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Cancer Chemotherapy ◽  
Antitumour Activity ◽  
Multidrug Resistant ◽  
The Novel ◽  
Mice Model ◽  
P Glycoprotein ◽  
Channel Currents

MDR (multidrug-resistance) represents a major obstacle to successful cancer chemotherapy and is usually accomplished by overexpression of P-gp (P-glycoprotein). Much effort has been devoted to developing P-gp inhibitors to modulate MDR. However, none of the inhibitors on the market have been successful. 1416 [1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (phenoprolamine hydrochloride)] is a new VER (verapamil) analogue with a higher IC50 for blocking calcium channel currents than VER. In the present paper, we examined the inhibition effect of 1416 on P-gp both in vitro and in vivo. 1416 significantly enhanced cytotoxicity of VBL (vinblastine) in P-gp-overexpressed human multidrug-resistant K562/ADM (adriamycin) and KBV cells, but had no such effect on the parent K562 and KB cells. The MDR-modulating function of 1416 was further confirmed by increasing intracellular Rh123 (rhodanmine123) content in MDR cells. Human K562/ADM xenograft-nude mice model verified that 1416 potentiates the antitumour activity of VBL in vivo. RT-PCR (reverse transcriptase-PCR) and FACS analysis demonstrated that the expression of MDR1/P-gp was not affected by 1416 treatment. All these observations suggest that 1416 could be a promising agent for overcoming MDR in cancer chemotherapy.

Abstract 531: Tie-2/Cre--Mediated Conditional Deletion of Lipid Phosphate Phosphatase-3 Reveals Its Role in Endothelial Cell Apoptosis

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Ishita Chatterjee ◽  
Kishore K Wary
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Genome Wide Association Study ◽  
Vascular Endothelial Cell ◽  
Protein Levels ◽  
Conditional Deletion ◽  
Transmission Electron ◽  
Increased Risk

Rationale: A recent genome-wide association study (GWAS) has linked a frequently occurring variation in the LPP3 (also known as PPAP2b) loci to increased risk of coronary heart disease (CAD). However, the in vivo function of LPP3 in vascular endothelial cell is incompletely understood. Goal: To address the endothelial cell (EC) specific function of Lpp3 in mice. Results: Tie-2/Cre mediated Lpp3 deletion did not affect normal vasculogenesis in early embryonic development, in contrast, in late embryonic stages it led to impaired angiogenesis associated with hemorrhage, edema and late embryonic lethal phenotype. Immunohistochemical staining followed by microscopic analyses of mutant embryos revealed reduced fibronectin and VE-cadherin expression throughout different vascular bed, and increased apoptosis in CD31+ vascular structures. Transmission electron microscopy (TEM) showed the presence of apoptotic endothelial cells and disruption of adherens junctions in mutant embryos. LPP3-knockdown in vitro showed an increase in p53 and p21 protein levels, with concomitant decrease in cell proliferation. LPP3-knockdown also decreased transendothelial electrical resistance (TER), interestingly re-expression of ß-catenin cDNA into LPP3-depleted endothelial cells partially restored the effect of loss of LPP3. Conclusion: These results suggest the ability of LPP3 to regulate survival and apoptotic activities of endothelial cells during patho/physiological angiogenesis.

scholarly journals Mutations in PA2491 (mexS) Promote MexT-Dependent mexEF-oprN Expression and Multidrug Resistance in a Clinical Strain of Pseudomonas aeruginosa

2005 ◽  
Vol 187 (4) ◽  
pp. 1246-1253 ◽  
Author(s):  
Mara L. Sobel ◽  
Shadi Neshat ◽  
Keith Poole
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Multidrug Resistance ◽  
Clinical Isolate ◽  
Multidrug Resistant ◽  
Clinical Strain ◽  
Insertion Mutant ◽  
Multidrug Efflux ◽  
Probable Significance

ABSTRACT Disruption of the PA2491 gene in a mini-Tn5-tet insertion mutant of a clinical isolate of Pseudomonas aeruginosa increased expression of the mexEF-oprN multidrug efflux genes and decreased production of outer membrane protein OprD, concomitant with enhanced resistance to chloramphenicol, quinolones, and imipenem, which was reminiscent of previously described nfxC mutants. PA2491 encodes a probable oxidoreductase previously shown to be positively regulated by the MexT positive regulator of mexEF-oprN expression (T. Köhler, S. F. Epp, L. K. Curty, and J. C. Pechére, J. Bacteriol. 181:6300-6305, 1999). Spontaneous multidrug-resistant mutants of the P. aeruginosa clinical isolate hyperexpressing mexEF-oprN and showing reduced production of OprD were readily selected in vitro, and all of them were shown to carry mutations in PA2491, highlighting the probable significance of such mutations as determinants of MexEF-OprN-mediated multidrug resistance in vivo.

scholarly journals Anlotinib Reverses Multidrug Resistance (MDR) in Osteosarcoma by Inhibiting P-Glycoprotein (PGP1) Function In Vitro and In Vivo

2022 ◽  
Vol 12 ◽  
Author(s):  
Gangyang Wang ◽  
Lingling Cao ◽  
Yafei Jiang ◽  
Tao Zhang ◽  
Hongsheng Wang ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Mouse Model ◽  
Atpase Activity ◽  
Multidrug Resistant ◽  
Chemotherapeutic Agents ◽  
Protein Expression Level ◽  
Nude Mouse Model ◽  
P Glycoprotein

Overexpression of the multidrug resistance (MDR)-related protein P-glycoprotein (PGP1), which actively extrudes chemotherapeutic agents from cells and significantly decreases the efficacy of chemotherapy, is viewed as a major obstacle in osteosarcoma chemotherapy. Anlotinib, a novel tyrosine kinase inhibitor (TKI), has good anti-tumor effects in a variety of solid tumors. However, there are few studies on the mechanism of anlotinib reversing chemotherapy resistance in osteosarcoma. In this study, cellular assays were performed in vitro and in vivo to evaluate the MDR reversal effects of anlotinib on multidrug-resistant osteosarcoma cell lines. Drug efflux and intracellular drug accumulation were measured by flow cytometry. The vanadate-sensitive ATPase activity of PGP1 was measured in the presence of a range of anlotinib concentrations. The protein expression level of ABCB1 was detected by Western blotting and immunofluorescence analysis. Our results showed that anlotinib significantly increased the sensitivity of KHOSR2 and U2OSR2 cells (which overexpress PGP1) to chemotherapeutic agents in vitro and in a KHOSR2 xenograft nude mouse model in vivo. Mechanistically, anlotinib increases the intracellular accumulation of PGP1 substrates by inhibiting the efflux function of PGP1 in multidrug-resistant cell lines. Furthermore, anlotinib stimulated the ATPase activity of PGP1 but affected neither the protein expression level nor the localization of PGP1. In animal studies, anlotinib in combination with doxorubicin (DOX) significantly decreased the tumor growth rate and the tumor size in the KHOSR2 xenograft nude mouse model. Overall, our findings suggest that anlotinib may be useful for circumventing MDR to other conventional antineoplastic drugs.

scholarly journals Manganese complex [Mn(CO)3(tpa-κ3N)]Br increases antibiotic sensitivity in multidrug resistant Streptococcus pneumoniae

2020 ◽  
Author(s):  
Apostolos Liakopoulos ◽  
Roberto M. La Ragione ◽  
Christoph Nagel ◽  
Ulrich Schatzschneider ◽  
Daniel E. Rozen ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Multidrug Resistance ◽  
Streptococcus Pneumoniae ◽  
Treatment Strategies ◽  
Antibiotic Sensitivity ◽  
Multidrug Resistant ◽  
Novel Treatment ◽  
Novel Treatment Strategies

AbstractThe emergence of multidrug-resistance (MDR) in Streptococcus pneumoniae clones and non-vaccine serotypes is of increasing concern, necessitating the development of novel treatment strategies. Here, we determined the efficacy of the Mn complex [Mn(CO)3(tpa-κ3N)]Br against MDR S. pneumoniae strains. Our data showed that [Mn(CO)3(tpa-κ3N)]Br has in vitro and in vivo antibacterial activity and has the potential to be used in combination with currently available antibiotics to increase their effectiveness against MDR S. pneumoniae.

Hydrolytically activated etoposide prodrugs inhibit MDR-1 function and eradicate established MDR-1 multidrug-resistant T-cell leukemia

Blood ◽  
2003 ◽  
Vol 102 (1) ◽  
pp. 246-253 ◽  
Author(s):  
Ulrike Schroeder ◽  
Kathrin M. Bernt ◽  
Björn Lange ◽  
Jens Wenkel ◽  
Jiang Jikai ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
T Cell ◽  
Multidrug Resistant ◽  
Leukemia Cell Line ◽  
Drug Resistant ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Mdr 1

Abstract Effective therapy of high-risk leukemia with established cytotoxic drugs may be limited by poor antitumor efficacy, systemic toxicity, and the induction of drug resistance. Here, we provide the first evidence that hydrolytically activated prodrugs may overcome these problems. For this purpose, VP16 was functionally blocked by hydrolytically cleavable carbonate linkers with unique characteristics to generate 2 novel prodrugs of VP16. First, we established a more than 3-log higher efficacy of the 2 prodrugs compared with VP16 on a panel of naturally drug-resistant tumor cell lines. Second, the prodrugs did overcome VP16-induced multidrug resistance-1 gene (MDR-1)—mediated multidrug resistance in vitro in a newly established VP16-resistant T-cell leukemia cell line MOVP-3 by functionally blocking MDR-1—mediated efflux. Third, in vivo studies showed a maximum tolerated dose of ProVP16-II (> 45mg/kg), which was at least 3-fold higher than that of VP16 (15 mg/kg). Finally, tests of ProVP16-II in a multidrug-resistant xenograft model of T-cell leukemia expressing MDR-1 indicated that only the mice treated with this prodrug revealed a complete and long-lasting regression of established, drug-resistant leukemia. In summary, the hydrolytically activated etoposide prodrugs proved effective against multidrug-resistant T-cell leukemia in vitro and in vivo and provide proof of concept for a highly promising new strategy for the treatment of MDR-1 drug-resistant malignancies. (Blood. 2003;102:246-253)

scholarly journals A novel cystathionine γ-lyase inhibitor, I194496, inhibits the growth and metastasis of human TNBC via downregulating multiple signaling pathways

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ya Liu ◽  
Lupeng Wang ◽  
Xiuli Zhang ◽  
Yuying Deng ◽  
Limin Pan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Anticancer Activity ◽  
Signaling Pathways ◽  
Nude Mice ◽  
High Capacity ◽  
Normal Breast ◽  
Inhibitory Effects ◽  
Protein Levels

AbstractTriple-negative breast cancer (TNBC) is a high-risk subtype of breast cancer with high capacity for metastasis and lacking of therapeutic targets. Our previous studies indicated that cystathionine γ-lyase (CSE) may be a new target related to the recurrence or metastasis of TNBC. Downregulation of CSE could inhibit the growth and metastasis of TNBC. The purpose of this study was to investigate the activity of the novel CSE inhibitor I194496 against TNBC in vivo and in vitro. The anticancer activity of I194496 in vitro were detected by MTS, EdU, and transwell assays. Methylene blue assay was used to determine the H2S level. Western blot was performed to analyze the expression of related pathway proteins. Xenograft tumors in nude mice were used to analyze the anticancer activity of I194496 in vivo. I194496 exerted potent inhibitory effects than l-propargylglycine (PAG, an existing CSE inhibitor) on human TNBC cells and possessed lower toxicity in normal breast epithelial Hs578Bst cells. I194496 reduced the activity and expression of CSE protein and the release of H2S in human TNBC cells. Meanwhile, the protein levels of PI3K, Akt, phospho (p)-Akt, Ras, Raf, p-ERK, p-Anxa2, STAT3, p-STAT3, VEGF, FAK, and Paxillin were decreased in human TNBC cells administrated with I194496. Furthermore, I194496 showed more stronger inhibitory effects on human TNBC xenograft tumors in nude mice. I194496 could inhibit the growth of human TNBC cells via the dual targeting PI3K/Akt and Ras/Raf/ERK pathway and suppress the metastasis of human TNBC cells via down-regulating Anxa2/STAT3 and VEGF/FAK/Paxillin signaling pathways. CSE inhibitor I194496 might become a novel and potential agent in the treatment of TNBC.

Magnetic Nanoparticle of Fe3O4 Loaded with Daunorubicin Reverse Leukemia Multidrug Resistance in Vivo

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5062-5062
Author(s):  
Bao-An Chen ◽  
Bin-bin Lai ◽  
Jian Cheng ◽  
Feng Gao ◽  
Wen-lin Xu ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Nude Mice ◽  
Magnetic Nanoparticle ◽  
Leukemia Cell ◽  
Multidrug Resistant ◽  
Leukemia Cell Line ◽  
Human Leukemia ◽  
Tumor Tissues ◽  
Fe3o4 Magnetic Nanoparticle

Abstract Object: To the effect of Fe3O4-magnetic nanoparticle loaded with DNR on In order to study the multidrug-resistant reversal effect of Fe3O4-magnetic nanoparticle loaded with DNR in vivo. Methods: K562-n,a leukemia cell line with high tumorigenicity in nude mice and its multidrug-resistant counterpart K562-n/VCR cells were inoculated subcutaneously into each groins of nude mice (5×106 cells/each) to establish a human leukemia xenograft model. The mice were randomly divided into group A receiving normal saline, group B receiving anti-tumor drugs daunorubicin (DNR), group C receiving Fe3O4-magnetic nanoparticle, group D receiving Fe3O4-magnetic nanoparticle loaded with DNR, and group E receiving Fe3O4-magnetic nanoparticle containing DNR with a magnetic field built on the surface of tumor tissues. After 20 days treatments, mice were killed and tumor tissues were isolated for pathological observation. The volume and weight of tumors were measured, then tumor suppression rate was calculated. The side effects of DNR loaded Fe3O4-magnetic nanoparticle were also evaluated. Results: The results showed that DNR loaded Fe3O4-magnetic nanoparticle can significantly suppress the growth of K562-n/VCR tumor in vivo, DNR alone can greatly suppress the growth of K562-n, Fe3O4-magnetic nanoparticle loaded with DNR can not further inhibit the K562-n tumor. Conclusion: In conclusion, Fe3O4-magnetic nanoparticle loaded with DNR can reverse the leukemia multidrug resistance in vivo.

Polyethylenimine-dextran-coated magnetic nanoparticles loaded with miR-302b suppress osteosarcoma in vitro and in vivo

Nanomedicine ◽  
2020 ◽  
Vol 15 (7) ◽  
pp. 711-723 ◽  
Author(s):  
Ming Gong ◽  
Huowen Liu ◽  
Ningxiang Sun ◽  
Yuanlong Xie ◽  
Feifei Yan ◽  
...  
Keyword(s):  
Nude Mice ◽  
Hippo Pathway ◽  
Inhibitory Effect ◽  
Transmission Electron ◽  
Potential Applications ◽  
Transport Carrier ◽  
Magnetic Transport ◽  
The Hippo Pathway

Aim: We attempted to synthesize a magnetic gene carrier with poly(ethylenimine), dextran and iron oxide nanoparticles (PDIs) for miR-302b transfection in vitro and in vivo. Materials & methods: The nanoparticles were characterized for hydrodynamic properties, ζ potential and DNA-binding ability, evaluated by transmission electron microscopy. Cellular internalization, magnetofection efficiency and anti-osteosarcoma effects were investigated in osteosarcoma (OS) cells and OS-bearing nude mice. Results: PDIs were successfully prepared and showed mild cytotoxicity. A magnetic field efficiently enabled transport of PDI/pmiR302b to OS cells in OS-bearing nude mice, exerting the anti-osteosarcoma effect of miR-302b at the tumor site. The inhibitory effect of miR-302b on osteosarcoma-bearing nude mice may be attributed to regulation of the Hippo pathway through YOD1. Conclusion: Low-cytotoxic PDIs have potential applications as a magnetic transport carrier for future osteosarcoma treatment.

scholarly journals Profiling and Characterization of Influenza Virus N1 Strains Potentially Resistant to Multiple Neuraminidase Inhibitors

2014 ◽  
Vol 89 (1) ◽  
pp. 287-299 ◽  
Author(s):  
Yun Hee Baek ◽  
Min-Suk Song ◽  
Eun-Young Lee ◽  
Young-il Kim ◽  
Eun-Ha Kim ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Multidrug Resistance ◽  
Influenza Virus Infection ◽  
Multidrug Resistant ◽  
Viral Fitness ◽  
Neuraminidase Inhibitors ◽  
Highly Pathogenic ◽  
Hpai H5n1

ABSTRACTNeuraminidase inhibitors (NAIs) have been widely used to control influenza virus infection, but their increased use could promote the global emergence of resistant variants. Although various mutations associated with NAI resistance have been identified, the amino acid substitutions that confer multidrug resistance with undiminished viral fitness remain poorly understood. We therefore screened a known mutation(s) that could confer multidrug resistance to the currently approved NAIs oseltamivir, zanamivir, and peramivir by assessing recombinant viruses with mutant NA-encoding genes (catalytic residues R152K and R292K, framework residues E119A/D/G, D198N, H274Y, and N294S) in the backbones of the 2009 pandemic H1N1 (pH1N1) and highly pathogenic avian influenza (HPAI) H5N1 viruses. Of the 14 single and double mutant viruses recovered in the backbone of pH1N1, four variants (E119D, E119A/D/G-H274Y) exhibited reduced inhibition by all of the NAIs and two variants (E119D and E119D-H274Y) retained the overall properties of gene stability, replicative efficiency, pathogenicity, and transmissibilityin vitroandin vivo. Of the nine recombinant H5N1 viruses, four variants (E119D, E119A/D/G-H274Y) also showed reduced inhibition by all of the NAIs, though their overall viral fitness was impairedin vitroand/orin vivo. Thus, single mutations or certain combination of the established mutations could confer potential multidrug resistance on pH1N1 or HPAI H5N1 viruses. Our findings emphasize the urgency of developing alternative drugs against influenza virus infection.IMPORTANCEThere has been a widespread emergence of influenza virus strains with reduced susceptibility to neuraminidase inhibitors (NAIs). We screened multidrug-resistant viruses by studying the viral fitness of neuraminidase mutantsin vitroandin vivo. We found that recombinant E119D and E119A/D/G/-H274Y mutant viruses demonstrated reduced inhibition by all of the NAIs tested in both the backbone of the 2009 H1N1 pandemic (pH1N1) and highly pathogenic avian influenza H5N1 viruses. Furthermore, E119D and E119D-H274Y mutants in the pH1N1 background maintained overall fitness propertiesin vitroandin vivo. Our study highlights the importance of vigilance and continued surveillance of potential NAI multidrug-resistant influenza virus variants, as well as the development of alternative therapeutics.

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