Emerging Therapies for Acute Myelogenus Leukemia Patients Targeting Apoptosis and Mitochondrial Metabolism

Castelli, Germana; Pelosi, Elvira; Testa, Ugo

doi:10.3390/cancers11020260

Cited by 27 publications

(23 citation statements)

References 402 publications

(700 reference statements)

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“…AG-221 (Enasidenib), a selective inhibitor of mutant IDH2, has demonstrated activity in pre-clinical models of acute myeloid leukemia (AML) [40][41][42] and is currently being assessed in multiple phases I/II clinical trials in subjects with advanced solid tumors, including iCCA, who harbor an IDH2 mutation (NCT02273739).…”

Section: Enasidenibmentioning

confidence: 99%

New and Emerging Systemic Therapeutic Options for Advanced Cholangiocarcinoma

Massironi

Pilla

Elvevi

et al. 2020

Cells

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Cholangiocarcinoma (CCA) represents a disease entity that comprises a heterogeneous group of biliary malignant neoplasms, with variable clinical presentation and severity. It may be classified according to its anatomical location and distinguished in intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA), each subtype implying distinct epidemiology, biology, prognosis, and strategy for clinical management. Its incidence has increased globally over the past few decades, and its mortality rate remains high due to both its biological aggressiveness and resistance to medical therapy. Surgery is the only potentially curative treatment and is the standard approach for resectable CCA; however, more than half of the patients have locally advanced or metastatic disease at presentation. For patients with unresectable CCA, the available systemic therapies are of limited effectiveness. However, the advances of the comprehension of the complex molecular landscape of CCA and its tumor microenvironment could provide new keys to better understand the pathogenesis, the mechanisms of resistance and ultimately to identify promising new therapeutic targets. Recently, clinical trials targeting isocitrate dehydrogenase (IDH)-1 mutations and fibroblast growth factor receptor (FGFR)-2 fusions, as well as immunotherapy showed promising results. All these new and emerging therapeutic options are herein discussed.

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Section: Enasidenibmentioning

confidence: 99%

New and Emerging Systemic Therapeutic Options for Advanced Cholangiocarcinoma

Massironi

Pilla

Elvevi

et al. 2020

Cells

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“…Acute myeloid leukemia (AML) is a malignant disease of the hematopoietic cells characterized by impaired differentiation and uncontrolled clonal expansion of myeloid progenitors/precursors, resulting in bone marrow (BM) failure and impaired normal hematopoiesis [1]. Currently, 40–50% of AML patients can be cured using conventional chemotherapy [2].…”

Section: Introductionmentioning

confidence: 99%

7-Ketocholesterol Promotes Oxiapoptophagy in Bone Marrow Mesenchymal Stem Cell from Patients with Acute Myeloid Leukemia

Paz

Levy

Oliveira

et al. 2019

Cells

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7-Ketocholesterol (7-KC) is a cholesterol oxidation product with several biological functions. 7-KC has the capacity to cause cell death depending on the concentration and specific cell type. Mesenchymal stem cells (MSCs) are multipotent cells with the ability to differentiate into various types of cells, such as osteoblasts and adipocytes, among others. MSCs contribute to the development of a suitable niche for hematopoietic stem cells, and are involved in the development of diseases, such as leukemia, to a yet unknown extent. Here, we describe the effect of 7-KC on the death of bone marrow MSCs from patients with acute myeloid leukemia (LMSCs). LMSCs were less susceptible to the death-promoting effect of 7-KC than other cell types. 7-KC exposure triggered the extrinsic pathway of apoptosis with an increase in activated caspase-8 and caspase-3 activity. Mechanisms other than caspase-dependent pathways were involved. 7-KC increased ROS generation by LMSCs, which was related to decreased cell viability. 7-KC also led to disruption of the cytoskeleton of LMSCs, increased the number of cells in S phase, and decreased the number of cells in the G1/S transition. Autophagosome accumulation was also observed. 7-KC downregulated the SHh protein in LMSCs but did not change the expression of SMO. In conclusion, oxiapoptophagy (OXIdative stress + APOPTOsis + autophagy) seems to be activated by 7-KC in LMSCs. More studies are needed to better understand the role of 7-KC in the death of LMSCs and the possible effects on the SHh pathway.

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“…Repurposing existing drugs in new combinations could provide new possibilities with reduced cost and time for development, while potentially minimizing side effects by lowering drug dosages (6). Mitochondrial dependency of leukemia cells and their altered oxidative metabolism have already been noticed as frequent abnormality existing in various AML subgroups (55,56). Moreover, several drug combinations based on mitotoxic drugs, such as cytarabine and mitoxantrone or cytarabine with anthracyclines (doxorubicin, etc.…”

Section: Discussionmentioning

confidence: 99%

Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy

et al. 2020

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Acute myeloid leukemia (AML) is an aggressive group of cancers with high mortality rates and significant relapse risks. Current treatments are insufficient, and new therapies are needed. Recent discoveries suggest that AML may be particularly sensitive to chemotherapeutics that target mitochondria. To further investigate this sensitivity, six compounds that target mitochondria [IACS-010759, rotenone, cytarabine, etoposide, ABT-199 (venetoclax), and carbonyl cyanide m-chlorophenylhydrazone] were each paired with six compounds with other activities, including tyrosine kinase inhibitors (midostaurin and dasatinib), glycolytic inhibitors (2-deoxy-D-glucose, 3-bromopyruvate, and lonidamine), and the microtubule destabilizer vinorelbine. The 36 resulting drug combinations were tested for synergistic cytotoxicity against MOLM-13 and OCI-AML2 AML cell lines. Four combinations (IACS-010759 with vinorelbine, rotenone with 2-deoxy-D-glucose, carbonyl cyanide m-chlorophenylhydrazone with dasatinib, and venetoclax with lonidamine) showed synergistic cytotoxicity in both AML cell lines and were selective for tumor cells, as survival of healthy PBMCs was dramatically higher. Among these drug pairs, IACS-010759/vinorelbine decreased ATP level and impaired mitochondrial respiration and coupling efficiency most profoundly. Some of these four treatments were also effective in K-562, KU812 (chronic myelogenous leukemia) and CCRF-CEM, MOLT-4 (acute lymphoblastic leukemia) cells, suggesting that these treatments may have value in treating other forms of leukemia. Finally, two of the four combinations retained high synergy and strong selectivity in primary AML cells from patient samples, supporting the potential of these treatments for patients.

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Emerging Therapies for Acute Myelogenus Leukemia Patients Targeting Apoptosis and Mitochondrial Metabolism

Cited by 27 publications

References 402 publications

New and Emerging Systemic Therapeutic Options for Advanced Cholangiocarcinoma

New and Emerging Systemic Therapeutic Options for Advanced Cholangiocarcinoma

7-Ketocholesterol Promotes Oxiapoptophagy in Bone Marrow Mesenchymal Stem Cell from Patients with Acute Myeloid Leukemia

Utilizing Synergistic Potential of Mitochondria-Targeting Drugs for Leukemia Therapy

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