scholarly journals Emodin and Its Combination with Cytarabine Induce Apoptosis in Resistant Acute Myeloid Leukemia Cells in Vitro and in Vivo

2018 ◽  
Vol 48 (5) ◽  
pp. 2061-2073 ◽  
Author(s):  
Yingyu Chen ◽  
Donghui Gan ◽  
Qinghua Huang ◽  
Xiaofeng Luo ◽  
Donghong Lin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Signaling Pathways ◽  
Myeloid Leukemia ◽  
Xenograft Model ◽  
Erk Signaling ◽  
Mouse Xenograft ◽  
Mouse Xenograft Model ◽  
Acute Myeloid

Background/Aims: Acute myeloid leukemia (AML) remains a hematologic malignancy with poor survival and a high risk of relapse, which is mainly caused by the emergence of multidrug resistance (MDR). The identification of novel agents to improve therapeutic strategies becomes important priority for AML treatment. It has been shown that emodin has therapeutic effects on many kinds of human malignant tumors. In this study, we investigated the anti-leukemia effects of emodin alone or in combination with cytarabine (Ara-C) on multidrug-resistant AML HL-60/ADR cells and in a mouse xenograft model of human highly tumorigenic AML HL-60/H3 cells. The underlying mechanism was also addressed. Methods: Cell viability after treatment was measured by MTT assay. The DNA fragmentation assay, Annexin V-PE/7-AAD, AO/EB staining, and electron microscopy were introduced to assess the apoptotic induction effects. Changes in protein expression in the Akt and ERK signaling pathways were determined by western blotting. In vivo antileukemia effects on HL-60/H3 xenograft model and overall mouse survival outcomes were further analyzed in this study. Results: Emodin dose-dependently induced growth inhibition and apoptotic effects in resistant HL-60/ADR cells in vitro as well as in the HL-60/H3 xenograft models in vivo. Moreover, emodin significantly enhanced chemosensitivity of AML cells to Ara-C, inhibited leukemic cell growth, and improved survival in the mouse xenograft model of AML. Dual targeting of Akt and ERK signaling pathways might contribute to the anti-leukemia effects on AML cells in vitro and in vivo. Conclusion: Emodin and its combination with Ara-C may be considered a promising therapeutic approach in AML and worthy of further investigation.

Pre-Clinical Activity of Amino-Alcohol Dimeric Naphthoquinones as Potential Therapeutics for Acute Myeloid Leukemia

2021 ◽  
Vol 21 ◽  
Author(s):  
Dana Ferraris ◽  
Rena Lapidus ◽  
Phuc Truong ◽  
Dominique Bollino ◽  
Brandon Carter-Cooper ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Amino Alcohol ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Xenograft Model ◽  
Clinical Activity ◽  
Lead Compound ◽  
Acute Myeloid

Background: The clinical outcomes of patients with acute myeloid leukemia (AML) remain unsatisfactory, therefore the development of more efficacious and better-tolerated therapy for AML is critical. We have previously reported the anti-leukemic activity of synthetic halohydroxyl dimeric naphthoquinones (BiQ) and aziridinyl BiQ. Objective: This study aimed to improve the potency and bioavailability of BiQ compounds and investigate the anti-leukemic activity of the lead compound in vitro and in a human AML xenograft mouse model. Methods: We designed, synthesized, and performed structure-activity relationship of several rationally designed BiQ analogues that possess amino alcohol functional groups on the naphthoquinone core rings. The compounds were screened for anti-leukemic activity and the mechanism as well as in vivo tolerability and efficacy of our lead compound was investigated. Results: We report that a dimeric naphthoquinone (designated BaltBiQ) demonstrated potent nanomolar anti-leukemic activity in AML cell lines. BaltBiQ treatment resulted in the generation of reactive oxygen species, induction of DNA damage, and inhibition of indoleamine dioxygenase 1. Although BaltBiQ was tolerated well in vivo, it did not significantly improve survival as a single agent, but in combination with the specific Bcl-2 inhibitor, Venetoclax, tumor growth was significantly inhibited compared to untreated mice. Conclusion: We synthesized a novel amino alcohol dimeric naphthoquinone, investigated its main mechanisms of action, reported its in vitro anti-AML cytotoxic activity, and showed its in vivo promising activity combined with a clinically available Bcl-2 inhibitor in a patient-derived xenograft model of AML.

scholarly journals A phenotypic screen identifies a compound series that induces differentiation of acute myeloid leukemia cells in vitro and shows anti-tumour effects in vivo

2020 ◽  
Author(s):  
Laia Josa-Culleré ◽  
Katrina S. Madden ◽  
Thomas J. Cogswell ◽  
Thomas R. Jackson ◽  
Tom S. Carter ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Xenograft Model ◽  
Tumour Volume ◽  
Specific Patient ◽  
Phenotypic Screen ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid

AbstractInduction of differentiation is a promising therapeutic strategy against acute myeloid leukemia. However, current differentiation therapies are effective only to specific patient populations. To identify novel differentiation agents with wider efficacy, we developed a phenotypic high-throughput screen with a range of genetically diverse cell lines. From the resulting hits, one chemical scaffold was optimised in terms of activity and physicochemical properties to yield OXS007417, which was also able to decrease tumour volume in a murine in vivo xenograft model.

scholarly journals Palbociclib and Ponatinib Suppress Acute Myeloid Leukemia in Patient-Derived Xenograft

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4461-4461
Author(s):  
Daniel Busa ◽  
Tomas Loja ◽  
Ivana Jeziskova ◽  
Adam Folta ◽  
Jiri Mayer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Disease Burden ◽  
Xenograft Model ◽  
Final Analysis ◽  
Lymphoid Leukemia ◽  
Patient Derived Xenograft ◽  
Acute Myeloid

Abstract Aims: Palbociclib, a breast cancer approved CDK4/6 inhibitor, and ponatinib, a BCR/ABL1 inhibitor with a multi-kinase activity approved for chronic myeloid and acute lymphoid leukemia, were previously shown to be effective in vitro against acute myeloid leukemia (AML). Here, we aimed to test this effect in a patient-derived xenograft model. Methods: Two newly diagnosed AMLs (AML #1: myelomonocytic AML, intermediate cytogenetic risk; AML #2: AML with myelodysplasia-related changes, poor cytogenetic risk) were xenotransplanted into NOD SCID gamma mice. Treatment was initiated at detection of approximately 5-20% hCD45+ cells in mouse peripheral blood (PB). Palbociclib, ponatinib, vehicle, and venetoclax as a comparative treatment, were administered orally for 3 weeks, 5 days per week. Chemotherapy (cytarabine+doxorubicine, AraC/Dox) 5+3 regimen served as a positive control. Azacitidine served as another comparative drug and was administered subcutaneously, five days per week in 3 cycles - 1 week on, 1 week off. Results: Significant reduction of disease burden and prolongation of overall survival (OS) were seen with palbociclib and the reference treatment venetoclax in both AMLs, and with chemotherapy in AML#1 (Fig. 1). Ponatinib prolonged OS in AML#1 but failed to provide reduction of disease burden in PB. Interestingly, azacitidine induced the longest remission (<1% hCD45+ cells in PB), for almost 10 weeks, but only in 2/4 mice for AML#2. Treatment toxicity manifested by weight decrease was only seen with chemotherapy (AML#1: 24% weight loss, p = 0.0001; AML#2: 19% loss, p = 0.04), and was also accompanied with early mouse mortality in 3/4 mice for AML#2. None of the tested treatments lead to complete AML eradication and a gradual relapse was seen in PB. The AML infiltration was higher in bone marrow than in spleen at final analysis at relapse (AML#1, 83 vs 73% of hCD45+ cells, mean, p = 0.02; AML#2, 95 vs 65%, p = 0.0001). No changes in AML phenotype were observed between treated and vehicle mice in case of AML#1, except for azacitidine which decreased monocyte (SSCdim, CD45high; 94 vs 96%, mean, p = 0.03), CD34+ (2 vs 5%, p = 0.01) and primitive CD34+CD38- cell (0.1 vs 0.3%, p = 0.005) percentages. For AML#2, blast (SSClow, CD45dim) percentage compared to vehicle (70%) was decreased by chemotherapy (24%, p = 0.01) and increased by venetoclax (80%, p = 0.03) and azacitidine (87%, p = 0.03); monocytes (6% for vehicle) were decreased by chemotherapy (1%, p = 0.004), venetoclax (3%, p = 0.01), and azacitidine (0%, p = 0.008); CD34+ cells were increased by venetoclax (59 vs 39%, p = 0.02). Summary: Palbociclib, and partially ponatinib, demonstrated AML suppression in vivo. This encourages further investigation of their efficacy in different AML subtypes and in combination with other drugs. Funding: Supported by MUNI/A/1595/2020. Figure 1 Figure 1. Disclosures Mayer: AOP Orphan Pharmaceuticals: Research Funding.

scholarly journals Oncogenic lncRNA ZNF561-AS1 is essential for colorectal cancer proliferation and survival through regulation of miR-26a-3p/miR-128-5p-SRSF6 axis

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Zizhen Si ◽  
Lei Yu ◽  
Haoyu Jing ◽  
Lun Wu ◽  
Xidi Wang
Keyword(s):  
Colorectal Cancer ◽  
Rna Binding ◽  
Xenograft Model ◽  
Luciferase Reporter ◽  
Cancer Proliferation ◽  
Mouse Xenograft ◽  
Mouse Xenograft Model

Abstract Background Long non-coding RNAs (lncRNA) are reported to influence colorectal cancer (CRC) progression. Currently, the functions of the lncRNA ZNF561 antisense RNA 1 (ZNF561-AS1) in CRC are unknown. Methods ZNF561-AS1 and SRSF6 expression in CRC patient samples and CRC cell lines was evaluated through TCGA database analysis, western blot along with real-time PCR. SRSF6 expression in CRC cells was also examined upon ZNF561-AS1 depletion or overexpression. Interaction between miR-26a-3p, miR-128-5p, ZNF561-AS1, and SRSF6 was examined by dual luciferase reporter assay, as well as RNA binding protein immunoprecipitation (RIP) assay. Small interfering RNA (siRNA) mediated knockdown experiments were performed to assess the role of ZNF561-AS1 and SRSF6 in the proliferative actives and apoptosis rate of CRC cells. A mouse xenograft model was employed to assess tumor growth upon ZNF561-AS1 knockdown and SRSF6 rescue. Results We find that ZNF561-AS1 and SRSF6 were upregulated in CRC patient tissues. ZNF561-AS1 expression was reduced in tissues from treated CRC patients but upregulated in CRC tissues from relapsed patients. SRSF6 expression was suppressed and enhanced by ZNF561-AS1 depletion and overexpression, respectively. Mechanistically, ZNF561-AS1 regulated SRSF6 expression by sponging miR-26a-3p and miR-128-5p. ZNF561-AS1-miR-26a-3p/miR-128-5p-SRSF6 axis was required for CRC proliferation and survival. ZNF561-AS1 knockdown suppressed CRC cell proliferation and triggered apoptosis. ZNF561-AS1 depletion suppressed the growth of tumors in a model of a nude mouse xenograft. Similar observations were made upon SRSF6 depletion. SRSF6 overexpression reversed the inhibitory activities of ZNF561-AS1 in vivo, as well as in vitro. Conclusion In summary, we find that ZNF561-AS1 promotes CRC progression via the miR-26a-3p/miR-128-5p-SRSF6 axis. This study reveals new perspectives into the role of ZNF561-AS1 in CRC.

scholarly journals Potentially Curative Therapeutic Activity of NEO212, a Perillyl Alcohol-Temozolomide Conjugate, in Preclinical Cytarabine-Resistant Models of Acute Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3385
Author(s):  
Axel H. Schönthal ◽  
Steve Swenson ◽  
Radu O. Minea ◽  
Hye Na Kim ◽  
Heeyeon Cho ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Side Effects ◽  
Anticancer Activity ◽  
Myeloid Leukemia ◽  
Perillyl Alcohol ◽  
Therapeutic Activity ◽  
Acute Myeloid

Despite progress in the treatment of acute myeloid leukemia (AML), the clinical outcome remains suboptimal and many patients are still dying from this disease. First-line treatment consists of chemotherapy, which typically includes cytarabine (AraC), either alone or in combination with anthracyclines, but drug resistance can develop and significantly worsen prognosis. Better treatments are needed. We are developing a novel anticancer compound, NEO212, that was created by covalent conjugation of two different molecules with already established anticancer activity, the alkylating agent temozolomide (TMZ) and the natural monoterpene perillyl alcohol (POH). We investigated the anticancer activity of NEO212 in several in vitro and in vivo models of AML. Human HL60 and U937 AML cell lines, as well as different AraC-resistant AML cell lines, were treated with NEO212 and effects on cell proliferation, cell cycle, and cell death were investigated. Mice with implanted AraC-sensitive or AraC-resistant AML cells were dosed with oral NEO212, and animal survival was monitored. Our in vitro experiments show that treatment of cells with NEO212 results in growth inhibition via potent G2 arrest, which is followed by apoptotic cell death. Intriguingly, NEO212 was equally potent in highly AraC-resistant cells. In vivo, NEO212 treatment strikingly extended survival of AML mice and the majority of treated mice continued to thrive and survive without any signs of illness. At the same time, we were unable to detect toxic side effects of NEO212 treatment. All in all, the absence of side effects, combined with striking therapeutic activity even in an AraC-resistant context, suggests that NEO212 should be developed further toward clinical testing.

scholarly journals ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

2016 ◽  
Vol 113 (43) ◽  
pp. E6669-E6678 ◽  
Author(s):  
Mark A. Gregory ◽  
Angelo D’Alessandro ◽  
Francesca Alvarez-Calderon ◽  
Jihye Kim ◽  
Travis Nemkov ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mitochondrial Oxidative Stress ◽  
Flt3 Inhibitor ◽  
A Genome ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy. We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.

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