scholarly journals Coinhibition of overexpressed genes in acute myeloid leukemia subtype M2 by gold nanoparticles functionalized with five antisense oligonucleotides and one anti-CD33(+)/CD34(+) aptamer

2016 ◽  
Vol 23 (9) ◽  
pp. 315-320 ◽  
Author(s):  
M A Zaimy ◽  
A Jebali ◽  
B Bazrafshan ◽  
S Mehrtashfar ◽  
S Shabani ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Acute Myeloid Leukemia ◽  
Antisense Oligonucleotides ◽  
Myeloid Leukemia ◽  
Acute Myeloid

Gelatin-coated Gold Nanoparticles as Carriers of FLT3 Inhibitors for Acute Myeloid Leukemia Treatment

2016 ◽  
Vol 87 (6) ◽  
pp. 927-935 ◽  
Author(s):  
Sorina Suarasan ◽  
Timea Simon ◽  
Sanda Boca ◽  
Ciprian Tomuleasa ◽  
Simion Astilean
Keyword(s):  
Gold Nanoparticles ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Flt3 Inhibitors ◽  
Leukemia Treatment ◽  
Acute Myeloid

Liposomal Bcl-2 antisense oligonucleotides enhance proliferation, sensitize acute myeloid leukemia to cytosine-arabinoside, and induce apoptosis independent of other antiapoptotic proteins

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3929-3938 ◽  
Author(s):  
Marina Konopleva ◽  
Ana M. Tari ◽  
Zeev Estrov ◽  
David Harris ◽  
Zhong Xie ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Antisense Oligonucleotides ◽  
Myeloid Leukemia ◽  
Down Regulation ◽  
Hematopoietic Stem ◽  
Antiapoptotic Proteins ◽  
Low Concentrations ◽  
Blast Cells ◽  
Induced Apoptosis ◽  
Acute Myeloid

Abstract The antiapoptotic proteins, Bcl-2 and Bcl-XL, are expressed in most cases of acute myeloid leukemia (AML) and may contribute to drug resistance in AML. We tested the hypothesis that down-regulation of Bcl-2 alone by antisense oligodeoxynucleotides (Bcl-2-AS) induces apoptosis, even in the presence of other antiapoptotic genes. We tested Bcl-2-AS in myeloid leukemic HL-60 cells, in Bcl-2 and Bcl-XL overexpressing HL-60-DOX cells, and in primary AML samples. Down-regulation of Bcl-2 by Bcl-2-AS reduced the viability of HL-60 cells and, less effectively, HL-60-DOX cells and increased ara-C cytotoxicity in both cell lines. Incubation of primary AML blasts with Bcl-2-AS decreased Bcl-2 expression in CD34+ blast cells after induction of apoptosis and enhancement of ara-C cytotoxicity in 11 of 19 primary AML samples. In 8 samples in which Bcl-2-AS did not induce apoptosis, baseline Bcl-2 levels were found to be strikingly high. The expression of other antiapoptotic proteins (Bcl-XL, Bag-1, A1, and Mcl-1) did not prevent Bcl-2-AS–induced apoptosis. Bcl-2-AS also inhibited colony formation of AML progenitor cells. Low concentrations of Bcl-2-AS induced significant increases in S-phase cells (P = .04). Results establish Bcl-2 as a critical target for AS strategies in AML in which the baseline levels predict response to Bcl-2-AS. Bcl-2 exerts both antiapoptotic and antiproliferative functions in AML. Because early normal hematopoietic stem cells do not express Bcl-2, Bcl-2-AS therapy should be highly selective for AML cells.

scholarly journals Drug-DNA Conjugated Gold Nanoparticles for the Treatment of Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4935-4935
Author(s):  
Nathan Gossai ◽  
Jordan Naumann ◽  
Ed Zamora ◽  
Nan-Sheng Li ◽  
Joseph Piccirilli ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Acute Myeloid Leukemia ◽  
T Cell Activation ◽  
Myeloid Leukemia ◽  
Cell Activation ◽  
Leukemia Cell ◽  
Leukemia Cells ◽  
Cd34 Cells ◽  
Acute Myeloid ◽  
Novel Therapeutic

Abstract INTRODUCTION: Novel therapies are needed for acute myeloid leukemia as only ~60% of children are cured despite maximally intensive cytotoxic chemotherapy. Functionalized gold nanoparticles (AuNP) are utilized for many biomedical applications and represent a potentially novel therapeutic approach in leukemia. We enhanced this technology by developing an AuNP system that selectively releases molecularly targeted drugs in leukemia cells. METHODS: AuNPs were functionalized with short, double-stranded oligonucleotides with sequence complementarity to genes overexpressed in or unique to a leukemia cell (e.g. survivin or AML/ETO). Only the anti-sense oligonucleotide is covalently bound to the nanoparticle via a thiol linker. Thus, after entering leukemia cells, the endogenous targeted oncogene mRNA can bind to its complementary sequence on the AuNP and displace the non-covalently bound oligonucleotide which, in our system, is conjugated to the multi-tyrosine kinase inhibitor dasatinib. As a binary reaction, the amount of dasatinib-conjugated oligonucleotide released from the nanoparticle is directly proportional to both the presence and abundance of the complementary mRNA present in a cell. We evaluated AuNP uptake into multiple AML cell lines, as well as normal hematopoietic cells. The effect of dasatinib-AuNPs on dasatinib-sensitive leukemia cell lines was evaluated using proliferation assays, annexin V staining, and cell colony assays. Toxicity in T-cells and CD34+ cells was assessed with T-cell activation and p-SRC assays, respectively. RESULTS: Conjugation of dasatinib to an oligonucleotide complementary to a region of the survivin gene did not perturb its ability to inhibit SRC and c-KIT kinases in vitro. Leukemia cells demonstrate highly efficient AuNP uptake when cultured alone or with up to a 100-1000 fold excess of normal bone marrow cells. Treatment of K562 leukemia cells, containing a BCR/ABL translocation and high levels of survivin mRNA, with dasatinib-AuNPs resulted in dose-dependent p-SRC and p-CRKL inhibition. Furthermore, K562 cells also showed significantly impaired proliferation, increased apoptosis, and formed fewer colonies in methylcellulose. Conversely, normal T-cells and CD34+ cells, which express less survivin than leukemia cells, were significantly less affected by dasatinib-AuNPs than dasatinib alone as measured by T-cell activation assays and p-SRC levels, respectively. CONCLUSIONS: This method of using functionalized AuNPs to deliver and activate dasatinib in leukemia cells augments drug efficacy while minimizing toxicity and thus represents a novel therapeutic strategy for AML. Ongoing work is underway to characterize the mechanism of preferential AuNP uptake in leukemia cells and assessing in vivo activity using a murine xenotransplantation model of leukemia. Disclosures No relevant conflicts of interest to declare.

Targeting epigenetic pathway with gold nanoparticles for acute myeloid leukemia therapy

Biomaterials ◽  
2018 ◽  
Vol 167 ◽  
pp. 80-90 ◽  
Author(s):  
Rong Deng ◽  
Na Shen ◽  
Yang Yang ◽  
Hongliang Yu ◽  
Shuping Xu ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Acute Myeloid
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