Induction of Cross-resistance to ABCB1 Substrates in Venetoclax-resistant Human Leukemia HL60 Cells

Background: Multidrug resistance (MDR) is one of the strategies developed by cancer cells to inhibit the anticancer potential of the majority of chemotherapeutic agents and almost results in treatment failure. Objective: This study aimed to evaluate the therapeutic potential of camel milk exosomes (CME) on multidrug-resistant human acute promyelocytic leukemia HL60 cells (HL60/RS) and to investigate whether this CME could potentiate the anticancer effect of Doxorubicin (DOX) and decrease its side effects. Results: CME alone or combined with DOX significantly induced HL60/RS cell viability loss, apoptosis, and cell cycle arrest at the G0/G1 phase, and downregulated MDR genes (Abcb1, Abcc1, Abcg2) as compared to cells treated with DOX alone. Additionally, CME and DOX co-treated nude mice had the lowest tumor volume, Abcb1, Abcc1, Abcg2, and Bcl2 expression, and the highest Bax and caspase3 expression in HL60/RS xenografts. This combined therapy also decreased DOX adverse effects as revealed by decreased liver damage enzymes and lipid peroxide (MDA) and increased hepatic antioxidant enzymes (SOD, CAT, GPx). Conclusion: CME increased sensitivity of HL60/RS to DOX through, at least in part, reduction of MDR genes, induction of apoptosis, and cell cycle arrest. Thus, CME may be used as safe adjuvants to DOX during cancer treatment. Keywords: Camel milk exosomes; Myeloid leukemia; HL60; Apoptosis; MDR

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Antitumor activities of Quercetin and Green Tea in xenografts of human leukemia HL60 cells

Scientific Reports ◽

10.1038/s41598-018-21516-5 ◽

2018 ◽

Vol 8 (1) ◽

Cited By ~ 26

Author(s):

Andrana Karla Calgarotto ◽

Victor Maso ◽

Gilberto Carlos Franchi Junior ◽

Alexandre Eduardo Nowill ◽

Paulo Latuf Filho ◽

...

Keyword(s):

Green Tea ◽

Human Leukemia ◽

Antitumor Activities ◽

Hl60 Cells

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Expression Pattern of Mitochondrial ND2 Gene in Human Leukemia and in HL60 Cells During Growth and Differentiation

Leukemia & Lymphoma ◽

10.3109/10428199109067635 ◽

1991 ◽

Vol 5 (5-6) ◽

pp. 397-406 ◽

Cited By ~ 2

Author(s):

Kazufumi Dohmen ◽

Jiro Kudo ◽

Ryuji Shimamura ◽

Hiroko Kondo ◽

Tsunefumi Shibuya ◽

...

Keyword(s):

Expression Pattern ◽

Human Leukemia ◽

Hl60 Cells ◽

Nd2 Gene

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Activation of protein kinase C prevents induction of apoptosis by geranylgeraniol in human leukemia HL60 cells

International Journal of Cancer ◽

10.1002/(sici)1097-0215(19970516)71:4<691::aid-ijc29>3.0.co;2-d ◽

1997 ◽

Vol 71 (4) ◽

pp. 691-697 ◽

Cited By ~ 13

Author(s):

Yutaka Masuda ◽

Madoka Yoda ◽

Hidekazu Ohizumi ◽

Toshihiro Aiuchi ◽

Masahiko Watabe ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Human Leukemia ◽

Hl60 Cells ◽

Kinase C ◽

Induction Of Apoptosis

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Characterization of the Resistance Mechanisms of HL60 Leukemia Cell Derivatives to Apo2L/TRAIL.

Blood ◽

10.1182/blood.v104.11.3412.3412 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3412-3412

Author(s):

Jinrong Cheng ◽

Bonnie L. Hylander ◽

Maria R. Baer ◽

Elizabeth A. Repasky

Keyword(s):

Cell Surface ◽

Tumor Cells ◽

Surface Expression ◽

Resistance Mechanisms ◽

Cell Surface Expression ◽

Caspase 8 ◽

Human Leukemia ◽

Resistant Clone ◽

Antibody Treatment ◽

Hl60 Cells

Abstract Tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is a recently identified member of the TNF superfamily. Recombinant Apo2L/TRAIL is a promising immunotherapeutic agent for treating malignant diseases since this molecule preferentially induces apoptosis in a variety of tumor cells with apparently little toxicity to normal cells. However, it has also been shown that some tumor cells are resistant to this molecule. We hypothesized that resistance to Apo2L/TRAIL occurs through defects in the Apo2L/TRAIL-mediated apoptotic signaling pathway. To address this hypothesis, we developed several Apo2L/TRAIL-resistant HL60 derivatives (HL60/TR) by exposure of Apo2L/TRAIL-sensitive HL60 human leukemia cells to escalating levels of Apo2L/TRAIL, followed by subcloning. Two of these resistant clones (a moderately resistant clone-R1 and a highly resistant clone-R3) were selected for further study. Molecules in the Apo2L/TRAIL-mediated apoptotic pathway of R1 and R3 cells were analyzed by Western blot analysis, flow cytometry and gene sequencing and compared to those in parental HL60 cells. In the R1 cells, the activation of caspase-8 and -10 by Apo2L/TRAIL was significantly inhibited. However, R1 cells were still sensitive to Fas agonistic monoclonal antibody treatment, indicating that the FAS-mediated apoptosis-inducing pathway was intact. In the R3 cells, caspase-8 expression was completely lost and activation of caspase-10 in response to Apo2L/TRAIL was totally inhibited; R3 cells were therefore also resistant to FAS antibody treatment. Although the total protein level of death receptors DR4 and DR5 was equal in HL60 cells and in the Apo2L/TRAIL-resistant derivatives, the cell surface levels of DR4 were significantly decreased in both R1 and R3 cells, while the surface expression level of DR5 in these two clones was comparable to that on HL60 cells. No mutation in either the DR4 or DR5 genes was found in these cells. These results suggest that defective targeting of DR4 molecules to the cell surface occurs in these Apo2L/TRAIL resistant cells. Blocking cell surface DR4 significantly attenuated the sensitivity of parental HL60 cells to Apo2L/TRAIL, indicating that cell surface expression of DR4 plays a crucial role in regulating susceptibility of tumor cells to Apo2L/TRAIL. Taken together, our results demonstrate that malignant cells can develop resistance to Apo2L/TRAIL by several different mechanisms and multiple resistance mechanisms may develop in a single tumor cell (such as R3 cells). Understanding the basis of Apo2L/TRAIL resistance will help to predict sensitivity and to develop strategies to circumvent resistance.

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Tumor Necrosis Factor-a Enhances Human Leukemia Cell Differentiation Induced by DMSO, but Not Retinoic Acid.

Blood ◽

10.1182/blood.v106.11.3893.3893 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3893-3893

Author(s):

Hong-Nu Yu ◽

Young-Rae Lee ◽

Hyun-Jaung Shim ◽

Myung-Kwan Han ◽

Eun-Kyung Song ◽

...

Keyword(s):

Retinoic Acid ◽

Tumor Necrosis ◽

Leukemia Cell ◽

Leukemia Cells ◽

Human Leukemia ◽

Induced Differentiation ◽

Cd11b Expression ◽

Hl60 Cells ◽

Reducing Activity ◽

Necrosis Factor

Abstract One of the human leukemia treatment methods is to differentiate leukemia cells into mature cells. Because differentiated cells lose their proliferative and tumor-forming abilities, differentiation inducers may be useful for the treatment of leukemia. Differentiation of leukemia cells has been studied using HL60 cells, a human promyelocytic leukemia cell line, which can be differentiated into granulocyte-like or monocyte/macrophage-like cells by various pharmacological agents such as dimethyl sulfoxide (DMSO), retinoic acid and phorbol myristic acetate (PMA). We previously reported that nuclear factor - kB (NF-kB) activation plays the important role in DMSO-induced differentiation of HL60 cells. Thus, we hypothesized that NF-kB activators could enhance DMSO-induced differentiation of HL60 cells. Here we examine whether tumor necrosis factor-a (TNF-a), a potent NF-kB inducer, enhance DMSO-induced differentiation of HL60 cells. TNF-a was found to enhance HL60 cell differentiation induced by DMSO. CD11b, a differentiation marker, was increased in 0.5 % DMSO-treated cells compared to control cells. When TNF-a was added to the same condition, CD11b expression was further enhanced in a dose and a time dependent manners. We also found that nitro blue tetrazolium (NBT) reducing activity, a marker for granulocytic differentiation, was further increased in DMSO plus TNF-a treated cells compared to only DMSO- treated cells. However, TNF-a alone had no effect on CD11b expression and NBT reducing activity. The enhancement of DMSO-induced HL60 differentiation by TNF-a was offset by NF-kB inhibition. Interestingly, retinoic acid- induced differentiation of HL60 cells showed no enhancing effect of TNF--a on the differentiation. These findings indicate that TNF--a might affect only NF-kB dependent differentation of HL60 cells. Taken together, we demonstrated that TNF-a enhances DMSO-induced differentiation of HL60 cells by stimulating NF-kB activation. Our results suggest that NF-kB inducers such as TNF-a are useful for the treatment of leukemia in combination with DMSO.

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Molecular mechanism of violacein-mediated human leukemia cell death

Blood ◽

10.1182/blood-2004-02-0594 ◽

2004 ◽

Vol 104 (5) ◽

pp. 1459-1464 ◽

Cited By ~ 78

Author(s):

Carmen Veríssima Ferreira ◽

Carina L. Bos ◽

Henri H. Versteeg ◽

Giselle Z. Justo ◽

Nelson Durán ◽

...

Keyword(s):

Molecular Mechanism ◽

Target Genes ◽

Human Lymphocytes ◽

Leukemia Cell ◽

Relevant Information ◽

Leukemic Cells ◽

Human Leukemia ◽

Tnf Receptor ◽

Hl60 Cells ◽

Tnf Α

Abstract Violacein, a pigment isolated from Chromobacterium violaceum in the Amazon River, presents diverse biologic properties and attracts interest as a consequence of its antileukemic activity. Elucidation of the molecular mechanism mediating this activity will provide further relevant information for understanding its effects on the cellular physiology of untransformed cells and for considering its possible clinical application. Here, we show that violacein causes apoptosis in HL60 leukemic cells but is ineffective in this respect in other types of leukemia cells or in normal human lymphocytes and monocytes. Violacein cytotoxicity in HL60 cells was preceded by activation of caspase 8, transcription of nuclear factor κB (NF-κB) target genes, and p38 mitogen-activated protein (MAP) kinase activation. Thus, violacein effects resemble tumor necrosis factor α (TNF-α) signal transduction in these cells. Accordingly, infliximab, an antibody that antagonizes TNF-α–induced signaling abolished the biologic activity of violacein. Moreover, violacein directly activated TNF receptor 1 signaling, because a violacein-dependent association of TNF receptor-associated factor 2 (TRAF2) to this TNF receptor was observed in coimmunoprecipitation experiments. Hence, violacein represents the first member of a novel class of cytotoxic drugs mediating apoptosis of HL60 cells by way of the specific activation of TNF receptor 1.

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