Clinical Application of Hypoxia-Inducible Factor-1α Inhibitors

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1		Zhengchao Wang	--	1806	2023-07-20 04:46:40	\|
2	format correct	Catherine Yang	+ 2 word(s)	1808	2023-07-20 07:13:11	\|

This entry is adapted from the peer-reviewed paper 10.3390/molecules27113426

Hypoxia is a common phenomenon amongst physiological and pathological conditions, and is a strong stressor for cells and organisms, which can lead to metabolic disorders, and even cause cell death. Hypoxia-inducible factor-1α (HIF-1α) is the only transcription factor that has been found to be active under hypoxia, and is also the main nuclear transcription factor that mediates the adaptive response to hypoxia in mammals. It is closely related to the growth and development of organisms and the pathogenesis of some diseases. HIF-1α has low expression in the human brain, lung, placenta, heart, skeletal muscle, kidney, and pancreas under normoxia, but there is an exponentially large increase of HIF-1α in the brain, lung, kidney, heart, and other tissues under hypoxia. HIF-1α inhibitors can be widely used in the treatment of various diseases related to HIF-1 overexpression, such as tumors; leukemia; diabetes and its complications; ischemic, cardiovascular and brain diseases; and inflammatory diseases, etc.

HIF-1α HIF-1α inhibitor tumor leukemia disease treatment

1. Anti-Tumor Therapy

The relationship between HIF-1α and tumors is a hot research topic at present. It has been found that HIF-1α is overexpressed in a variety of human cancers, including bladder, liver, breast, lung, osteosarcoma, glioma, ovarian, prostate, colon, and renal cell carcinoma ^[1]^[2]^[3]. During the occurrence and development of tumors, the growth speed of malignant tumor cells is uncontrolled and too fast, while the rate of tumor angiogenesis is relatively lagging, finally resulting in insufficient blood supply and widespread hypoxia in the tumor. HIF-1α is the main hypoxia response factor, so this anoxic environment leads to the increase of HIF-1α expression ^[4]. It has been reported that the expression level of HIF-1α in tumor specimens is positively correlated with the aggressiveness and poor prognosis for cancer patients with conventional therapy ^[5]. HIF-1 activates the transcription of genes involved in key aspects of cancer biology, and regulates the expression of many downstream genes, including hypoxic energy metabolism (PDK1 and LDHA), angiogenesis (VEGF and EPO), intracellular matrix remodeling (MMP1 and LOX), apoptosis/autophagy (BNIP3 and NIX), cell survival (Myc and IGF family) and cell invasion/migration and escape (CXCR4), etc. All of these make tumor cells resistant to hypoxia, and increase oxygen/energy supply, thereby promoting tumor growth, invasion, and metastasis ^[6]^[7]. In preclinical studies, inhibition of HIF-1α activity by various methods and down-regulation of various HIF-1α-mediated gene expressions have shown a significant impact on tumor growth. Therefore, the use of specific small-molecule inhibitors targeting HIF-1α is an attractive strategy for developing cancer therapeutics ^[8]. Efforts are currently underway to identify HIF-1α specific inhibitors and examine their efficacy as anticancer therapeutics.

Preclinical studies have confirmed that echinomycin has antitumor activity in liver cancer, breast cancer, colon cancer, and other diseases. Manassantin A and Manassantin B have strong selective inhibitory effects on human breast cancer T47D cells, and also have strong inhibitory effects on secretion of hypoxia-induced VEGF, CDKN1A, and GLUT-1 genes ^[9]^[10]. Studies have shown that curcumin and its derivative EF-24 have the effect of inhibiting tumor blood-vessel growth and delaying tumor growth ^[11]^[12]. YC-1 is a targeted HIF-1α inhibitor, which can resist intravascular thrombosis, block the hypoxia signaling pathway of cells, inhibit the expressions of HIF-1α and VEGF, inhibit tumor angiogenesis, and tumor cell proliferation, thereby exerting anti-tumor and anti-angiogenic effects ^[13]^[14]. Therefore, YC-1 can also be used to treat various diseases related to the overexpression of HIF-1α, such as angiogenesis-related diseases, immune disorders, cardiovascular remodeling, and pulmonary hypertension ^[15]^[16]^[17]. Sun et al. confirmed that intratumoral HIF-1α expression was inhibited by the transfection of antisense HIF-1α gene plasmid, resulting in the downregulation of VEGF and the reduction of intratumoral vascular density ^[18]. In addition, two applicable HIF-1α cDNA variants were recently discovered, both of which have bHLH and PAS domains, but lack the ODDD and TAD domains, one is HIF-1αZ, which is induced by zinc and competitively dimerizes with HIF-1β to inhibit the activity of HIF-1α, but does not block the nuclear translocation of endogenous HIF-1α ^[19]; the other is HIF-1α alternative splicing variant HIF- 1α516, a translated polypeptide of 516 amino acid residues, which also inhibits HIF-1α activity by competing with endogenous HIF-1α and binding to HIF-1β ^[20].

2. Leukemia Therapy

Various types of leukemia have an abnormally high expression of the HIF-1α gene, so the study of HIF-1α inhibitors may become a new strategy for the treatment of leukemia. In chronic lymphocytic leukemia (CLL), HIF-1α promotes bone marrow neovascularization, regulates the expression of chemokine receptors and cell adhesion molecules (such as CXCR 4, CXCL 12, etc.), thereby maintaining CLL cells survival within the bone marrow microenvironment ^[21]. Abdul-Aziz et al. ^[22] found that silencing HIF-1α inhibited the transcriptional regulation of metastasis suppressor factor (MIF) in AML cells in bone marrow under hypoxic conditions, thereby improving the survival of AML cells, indicating the pivotal role of the hypoxia/HIF-1α/MIF axis in promoting the survival and proliferation of an AML tumor. Zhang et al. ^[23] found that deficiency of HIF-1α in chronic myeloid leukemia (CML) resulted in increased expression of the cell cycle inhibitors (p16InK4a, p19Arf, and p57) and the apoptosis gene (p53) in leukemia stem cells (LSC). Ng et al. ^[24] demonstrated that the maintenance of CML stem cells under hypoxic conditions is dependent on HIF-1α by silencing HIF-1α gene. In patients with T-cell acute lymphoblastic leukemia (T-ALL), HIF-1α is overexpressed, and HIF-1α can promote the activation of Notch1 signaling, increase the expression of cyclin D1, CDK2, p21, MMP2, and MMP9 proteins, thereby leading to cell proliferation, invasion, and resistance ^[25]^[26]. Few data are available on the role of HIF-1α in acute B-lymphoblastic leukemia, but it has been demonstrated that HIF-1α expression is induced by leukemic B cells in the bone marrow ^[27].

Valsecchi et al. treated CLL with EZN-2208 and found that EZN-2208 can significantly inhibit the expression of HIF-1α, thereby impairing the directed chemotaxis of CXCL 12 in CLL cells, and induce cell death and prolong the survival time of mice with significant anti-leukemia activity ^[21]^[28]^[29]. In addition to being an anticancer agent, 2-ME2 also has anti-leukemia activity. The possible mechanisms of action include inhibiting the accumulation of superoxide dismutase (SOD) and reactive oxygen species (ROS), increasing the expressions of p53 and p21, and promoting the growth of cells in G2/M-phase cell cycle arrest, etc., thereby inhibiting the levels of HIF-1α, microtubules and tumor angiogenesis ^[30]. In all, 2-ME2 can inhibit the translation of MYC, a downstream effector of Notch1, and prevent the activity of SCL/TAL1, thereby eliminating the self-renewal activity of pre-leukemia stem cells. It can also block the G2/M-phase cell cycle, causing acute T lymphocytes to show typical apoptotic changes ^[30]^[31]. Similarly, in AML, 2-ME2 can inhibit the expressions of HIF-1α, VEGF, GLUT1, and HO-1.

Although the research on HIF-1α inhibitors in leukemia is at an early stage, based on the deepening research and the functional analysis of hypoxia-inducible factor in leukemia in the existing literature, HIF-1α inhibitors are expected to be a reliable treatment option for leukemia patients.

3. Diabetes and Its Complications

In diabetic tissues, hypoxia triggered by insufficient activation of HIF-1α signaling and impaired adaptive responses to hypoxia are fundamental pathogenic factors during the development of diabetes and diabetic complications ^[32]. Hyperglycemia-induced methylglyoxal modifies p300 and disrupts the binding of p300 to HIF-1α, thereby leading to the destabilization of HIF-1α and the downregulation of HIF-1α-related responses under hypoxic conditions ^[33]. Paradoxically, hyperglycemia also activates HIF-1α signaling in glomerular mesangial cells, suggesting that HIF-1α regulation is context-specific in diabetes ^[34]. In addition, HIF-1α is also associated with the development of microvascular and macrovascular complications in diabetes ^[35]. Therefore, strategies aimed at modulating HIF-1α signaling may be promising new treatments for diabetes and its complications.

Studies have shown that the use of deferoxamine (DFO) can eliminate methylglyoxal binding, correct high glucose-induced impairment of HIF-1α/p300 binding, and normalize the transactivation of HIF-1α ^[33]. According to the results of numerous studies, curcumin has also been used to treat diabetes and alleviate its complications by targeting multiple pathways ^[36].

4. Ischemic Cardiovascular and Cerebral Disease

In recent years, both basic and clinical studies have shown that myocardial ischemia and cerebral ischemia can significantly increase the expressions of HIF-1α mRNA and protein, which are undetectable in normal ventricular myocardium. Experimental evidence has shown that HIF-1α plays a key role in the protective effect of ischemic preconditioning in both myocardial and cerebral ischemic injury. In a femoral artery ligation model with HIF-1α gene knockout, it was found that vascular growth factors such as VEGF were not activated, and the ability of reperfusion after ischemia was reduced ^[37]. The proangiogenic effect of HIF-1α has also been found in injury models such as myocardial hypertrophy, myocardial infarction, and wound healing ^[38]^[39]. Therefore, in view of the important role of HIF-1α in various ischemic diseases, it may provide a new and effective therapeutic approach for diseases characterized by hypoxia, which has attracted extensive attention of scholars. Studies have found that S-nitrosoglutathione (GSNO) treatment stabilizes HIF-1α and induces the downstream gene expression of HIF-1α targets to stimulate regenerative processes, resulting in functional recovery in animals with mild traumatic brain injury ^[40].

5. Other Disorders

The expression of HIF-1α can be detected in inflammatory diseases such as immune inflammation, bacterial infection, macrophage metabolism and viral infection, as well as in corresponding inflammatory sites in patients with arthritis, arteriosclerosis, and autoimmune diseases. When inflammation occurs, local vascular permeability is enhanced, causing immune cells to aggregate at the site of inflammation, in a rapidly hypoxic environment, which in turn induces immune cells to transcribe HIF-1α. HIF-1α plays a key role in the synthesis of pro-inflammatory factor interleukin-1β (IL-1β) ^[41]. In macrophages and neutrophils, HIF-1α can activate NF-κB ^[42]. A compound extracted from celery, 3-N-Butylphthalide (NBP), may have anti-inflammatory effects by inhibiting the formation of HIF-1α transcriptional complex ^[43].

Many studies have also found that HIF-1α plays a certain role in the pathogenesis of rheumatoid arthritis (RA). Hu et al. found that HIF-1α makes the relationship between RA synovial fibroblasts (RASFs) and T/B cells persistent ^[44]. HIF-1α interacts to induce the production of inflammatory cytokines and autoantibodies, thereby aggravating the development of RA ^[42]. Similarly, Hu et al. also found that HIF-1α can enhance the expression of IL-8, IL-33, MMP, and VEGF in RASFs ^[45], which aggravates inflammation, cartilage destruction, and angiogenesis, and participates in the pathogenesis of RA.

HIF-1α is also involved in the pathogenesis of systemic lupus erythematosus (SLE). HIF-1α can induce SLE by affecting the ratio of Th17 and Treg cells, thereby causing an immune imbalance between these two cells ^[46]. Induced proliferation-related signaling protein 1 can cause pathological changes in the kidneys of SLE patients by regulating the expression of HIF-1α ^[47]. MiRNA-210 regulates the expression of HIF-1α and the differentiation of Th17 cells when the body is under hypoxic condition, destroying the body function of SLE patients ^[48]. These findings suggest that HIF-1α may be a new diagnostic marker for SLE. Although there are few applications of HIF-1α inhibitors in the treatment of SLE at present, in-depth research on HIF-1α inhibitors will lay an evidence-based medical foundation for the development of HIF-1α-targeted SLE treatment.

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