Roles of the hypoxia response system in hematopoietic and leukemic stem cells

Takubo, Keiyo; Suda, Toshio

doi:10.1007/s12185-012-1071-4

Cited by 40 publications

(33 citation statements)

References 38 publications

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“…Hypoxia has also increasingly been implicated in leukemia stem cell biology (37). We noted that in vitro TH-302 treatment decreased numbers of primary AML colonies under hypoxia.…”

Section: Discussionmentioning

confidence: 84%

Activity of the Hypoxia-Activated Prodrug, TH-302, in Preclinical Human Acute Myeloid Leukemia Models

Portwood

Lal

Hsu

et al. 2013

Clinical Cancer Research

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Purpose: Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm. Recent evidence has shown the bone marrow microenvironment in patients with AML to be intrinsically hypoxic. Adaptive cellular responses by leukemia cells to survive under low oxygenation also confer chemoresistance. We therefore asked whether therapeutic exploitation of marrow hypoxia via the hypoxia-activated nitrogen mustard prodrug, TH-302, could effectively inhibit AML growth.Experimental Design: We assessed the effects of hypoxia and TH-302 on human AML cells, primary samples, and systemic xenograft models.Results: We observed that human AML cells and primary AML colonies cultured under chronic hypoxia (1% O 2 , 72 hours) exhibited reduced sensitivity to cytarabine-induced apoptosis as compared with normoxic controls. TH-302 treatment resulted in dose-and hypoxia-dependent apoptosis and cell death in diverse AML cells. TH-302 preferentially decreased proliferation, reduced HIF-1a expression, induced cell-cycle arrest, and enhanced double-stranded DNA breaks in hypoxic AML cells. Hypoxia-induced reactive oxygen species by AML cells were also diminished. In systemic human AML xenografts (HEL, HL60), TH-302 [50 mg/kg intraperitoneally (i.p.) 5 times per week] inhibited disease progression and prolonged overall survival. TH-302 treatment reduced the number of hypoxic cells within leukemic bone marrows and was not associated with hematologic toxicities in nonleukemic or leukemic mice. Later initiation of TH-302 treatment in advanced AML disease was as effective as earlier TH-302 treatment in xenograft models.Conclusions: Our results establish the preclinical activity of TH-302 in AML and provide the rationale for further clinical studies of this and other hypoxia-activated agents for leukemia therapy.

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“…Hypoxia has also increasingly been implicated in leukemia stem cell biology (37). We noted that in vitro TH-302 treatment decreased numbers of primary AML colonies under hypoxia.…”

Section: Discussionmentioning

confidence: 84%

Activity of the Hypoxia-Activated Prodrug, TH-302, in Preclinical Human Acute Myeloid Leukemia Models

Portwood

Lal

Hsu

et al. 2013

Clinical Cancer Research

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“…In the axial skeleton, hematopoiesis continues into adulthood, but there is fatty infiltration of the vertebral bodies with aging (101). Changes in mammalian HSCs may affect the progression of MSCs into osteoblasts or adipocytes (104,105,106). For example, low bone mass is a feature of individuals with hemolytic anemia, a clinical condition associated with enhanced marrow adiposity (107)(108)(109).…”

Section: Cellular Interactionsmentioning

confidence: 99%

Bone Remodeling and Energy Metabolism: New Perspectives

Paula

Rosen

2013

Bone Res.

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Bone mineral, adipose tissue and energy metabolism are interconnected by a complex and multilevel series of networks. Calcium and phosphorus are utilized for insulin secretion and synthesis of high energy compounds. Adipose tissue store lipids and cholecalciferol, which, in turn, can influence calcium balance and energy expenditure. Hormones long-thought to solely modulate energy and mineral homeostasis may influence adipocytic function. Osteoblasts are a target of insulin action in bone. Moreover, endocrine mediators, such as osteocalcin, are synthesized in the skeleton but regulate carbohydrate disposal and insulin secretion. Finally, osteoblasts and adipocytes originate from the same mesenchymal progenitor. The mutual crosstalk between osteoblasts and adipocytes within the bone marrow microenvironment plays a crucial role in bone remodeling. In the present review we provide an overview of the reciprocal control between bone and energy metabolism and its clinical implications.

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“…2 Hypoxic maintenance of HSCs stabilizes the hypoxia-inducible factor (HIFa) proteins, which in turn play a vital role in preserving their functionality. 7,8 The activity of the ubiquitously expressed HIF1a protein is primarily regulated by the oxygen-dependent HIF prolyl hydroxylase domain proteins (PHD1-3). These enzymes hydroxylate distinct proline sites on HIFa, followed by ubiquitination by an E3 ubiquitin ligase complex containing the von Hippel-Lindau protein (pVHL) and proteasomal degradation.…”

Section: Introductionmentioning

confidence: 99%