Anti-angiogenic Effects Of Thalidomide Research Articles

Potential Therapeutic Uses of Thalidomide for Pulmonary Fibrosis

Thalidomide was widely used to avoid morning sickness in pregnant women, but was recalled due to its teratogenic effects and malformations in thousands of children. However, potential beneficial effects such as anti-inflammatory, system regulatory activities and the anti-angiogenic effect of thalidomide have been reported. As the studies about thalidomide continued, its new effects and applications made researchers more interested in it and became a promising agent in the treatment of a variety of clinical situations where standard treatments have failed. To make this purpose more achievable, Scopus, Science Direct, Google Scholar, and PubMed were searched. After obtaining and reviewing articles related to thalidomide and its indications, different therapeutic uses of thalidomide for pulmonary diseases are classified on mechanisms. In recent years, thalidomide has been an effective agent in treating cough associated with pulmonary fibrosis and the main suggested mechanism refers to regulation production of inflammatory mediators, including cytokines and chemokines, which trigger Epithelial-Mesenchymal Transition (EMT). The mechanism of EMT is related to the inhibition of Transforming growth factor-beta (TGF-β1)-mediated signaling pathways, Smad2 (Suppressor of Mothers against decapentaplegic homolog 2) / 3, Akt / Glycogen synthase kinase 3 beta (GSK-3β), and Mitogen-activated protein kinase (MAPK). Thalidomide is also involved in paraquat-induced and bleomycin-induced pulmonary fibrosis. Also, Thalidomide gained attention as a suitable agent for the treatment of cough associated with idiopathic pulmonary fibrosis (IPF) and for severe pulmonary damage cause by severe acute respiratory syndrome, coronavirus 2 (SARS-CoV-2), responsible for the global pandemic in 2020, due to its anti-inflammatory-anti-angiogenesis and pro-apoptotic properties.

Palladium (II) complex and thalidomide intercept angiogenic signaling via targeting FAK/Src and Erk/Akt/PLCγ dependent autophagy pathways in human umbilical vein endothelial cells.

The current study assessed the effects of the thalidomide and palladium (II) saccharinate complex of terpyridine on the suppression of angiogenesis-mediated cell proliferation. The viability was assessed after treatment with palladium (II) complex (1.56-100μM) and thalidomide (0.1-400μM) alone by using ATP assay for 48h. Palladium (II) complex was found to inhibit growth statistically significant in a dose-dependent manner in HUVECs and promoted PARP-1 cleavage through the production of ROS. On the other hand, thalidomide did not cause any significant change in cell viability. Moreover, cell death was observed to be manifested as late apoptosis due to Annexin V/SYTOX staining after palladium (II) complex treatment however, thalidomide did not demonstrate similar results. Thalidomide and palladium (II) complex also suppressed HUVEC migration and capillary-like structure tube formation in vitro in a time-dependent manner. Palladium (II) complex (5mg/ml) treatment showed a strong antiangiogenic effect similar to positive control thalidomide (5mg/ml) and successfully disrupted the vasculature and reduced the thickness of the vessels compared to control (agar). Furthermore, suppression of autophagy enhanced the cell death and anti-angiogenic effect of thalidomide and palladium (II) complex. We also showed that being treated with thalidomide and palladium (II) complex inhibited phosphorylation of the signaling regulators downstream of the VEGFR2. These results provide evidence for the regulation of endothelial cell functions that are relevant to angiogenesis through the suppression of the FAK/Src/Akt/ERK1/2 signaling pathway. Our results also indicate that PLC-γ1 phosphorylation leads to activation of p-Akt and p-Erk1/2 which cause stimulation on cell proliferation at lower doses. Hence, we demonstrated that palladium (II) and thalidomide can induce cell death via the Erk/Akt/PLCγ signaling pathway and that this pathway might be a novel mechanism.

Thalidomide therapy for refractory mucosal disease: benefit and risks over 10 years

<h3>Background</h3> The immunomodulatory and antiangiogenic effects of thalidomide have been demonstrated in a number of refractory ulcerative oromucosal conditions, including recurrent aphthous stomatitis (RAS), Behçet disease, erythema multiforme (EM), erosive lichen planus, and orofacial granulomatosis (OFG). Thalidomide acts by modulating the inflammatory cascade, interacting with various cytokines, including tumor necrosis factor-α, interleukin 10, and cyclooxygenase 2. Despite its efficacy, thalidomide is associated with a number of risks, including peripheral neuropathy, thromboembolic disease, and embryofetal toxicity, which limit its clinical use. <h3>Methods</h3> A retrospective review of the clinical database of the Oral Medicine Department at the Royal National ENT and Eastman Dental Hospitals, UCLH, London, UK, was undertaken to identify patients prescribed thalidomide between 2009 and 2019. <h3>Results</h3> Sixteen patients (9 men and 7 women) with a mean age of 46 years (range, 20-66 years) were identified in this cohort. Clinical diagnoses included RAS (n = 10), human immunodeficiency virus (HIV)-related oral ulceration (n = 3), EM (n = 2), and OFG (n = 1). All patients, with the exception of HIV-related cases, had proved refractory to systemic corticosteroids and/or immunosuppressive therapy. Patients were treated for a mean of 50 months (range, 1-120 months) with doses ranging from 50 mg every 3 days to 100 mg daily. A complete remission (CR) rate of 56% was noted in this cohort, with CR defined as complete clearing of mucosal disease within 1 month of treatment onset and maintenance of this CR during the second month of treatment. All patients underwent a baseline sensory nerve action potential test before initiating thalidomide. Five of 16 patients subjectively reported transient peripheral neuropathy. There was objective evidence of mild length-dependent axonal sensory neuropathy in 2 of 16 patients, with treatment cessation occurring in an isolated case due to persistent neuropathy. <h3>Conclusions</h3> Within this cohort, thalidomide demonstrated a favorable efficacy/safety ratio with long-term use. It remains a viable treatment option for cases of refractory oral ulceration. Given the history of adverse effects associated with thalidomide, informed consent with regard to embryofetal toxicity and contraceptive counseling are pivotal to safe prescribing. Counseling with respect to other common adverse effects, including peripheral neuropathy and venous and arterial thromboembolism, is mandatory, and these adverse effects need to be understood.

Redox Stimulation of CardiomyogenesisVersusInhibition of Vasculogenesis Upon Treatment of Mouse Embryonic Stem Cells with Thalidomide

Thalidomide [α-(N-phthalimido)-glutarimide] exerts antiangiogenic properties and causes cardiac malformations in embryos. Herein the effects of thalidomide on cardiovascular differentiation were investigated in mouse embryonic stem (ES) cell-derived embryoid bodies. Thalidomide inhibited the formation of capillary-like blood vessels and decreased tumor-induced angiogenesis in confrontation cultures of embryoid bodies and multicellular prostate tumor spheroids, but stimulated cardiomyogenesis of ES cells. The number of CD31- and CD144-positive endothelial cells was not impaired, suggesting that thalidomide acted on vascular tube formation and cell migration rather than endothelial differentiation. Thalidomide increased reactive oxygen species generation, which was abolished by the NADPH oxidase inhibitor VAS2870 and the complex I respiratory chain inhibitor rotenone. Conversely, thalidomide decreased nitric oxide (NO) generation and endothelial NO synthase activity. VAS2870 abrogated thalidomide stimulation of cardiomyogenesis, whereas inhibition of vasculogenesis persisted. In NOX-1 and NOX-4 shRNA gene-inactivated ES cells, cardiomyogenesis was severely impaired and thalidomide failed to stimulate cardiac cell commitment. The NO donor S-nitrosopenicillamine reversed the antiangiogenic effect of thalidomide and increased capillary structure formation, whereas scavenging NO by 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide and inhibition of endothelial NO synthase by N(G)-nitro-l-arginine methyl ester decreased cardiovascular differentiation. Our data demonstrate that thalidomide causes an imbalance of reactive oxygen species/NO generation, thus stimulating cardiomyogenesis and impairing vascular sprout formation.

Promoting the Pericyte: Modeling the Anti-Angiogenic Effects of Thalidomide in HHT

Promoting the Pericyte: Modeling the Anti-Angiogenic Effects of Thalidomide in HHT

Monotherapy with thalidomide for treatment of spinal cord hemangioblastomas in a patient with von Hippel–Lindau disease

Von Hippel-Lindau (VHL) disease is a cancer-prone syndrome characterized by abnormalities in vascular proliferation and the development of both the visceral and CNS tumors. Complications from hemangioblastoma are among the principal causes of death from this syndrome. Antiangiogenic therapy has been used with different modalities in patients suffering from such complications. Here, we describe an adolescent with VHL complicated by progressive, multifocal spinal hemangioblastomas. Treatment with single-agent thalidomide over the course of 3 years was associated with an unexpected stabilization of the disease. The antiangiogenic effect of thalidomide may be associated with the control of progressive hemangioblastoma.

Thalidomide: a treatment option for bleeding GI angiodysplasias in dialysed patients.

Thalidomide: a treatment option for bleeding GI angiodysplasias in dialysed patients.

Combination of thalidomide and cisplatin in an head and neck squamous cell carcinomas model results in an enhanced antiangiogenic activity in vitro and in vivo

Thalidomide is an immunomodulatory, antiangiogenic drug. Although there is evidence that it might be more effective in combination with chemotherapy the exact mechanism of action is unclear. Therefore, we investigated its effect in combination with metronomically applied cisplatin in a xenotransplant mouse model characteristic for advanced head and neck squamous cell carcinomas, its possible synergistic action in vitro, and which tumor-derived factors might be targeted by thalidomide. Although thalidomide alone was ineffective, a combined treatment with low-dose cisplatin inhibited significant tumor growth, proliferation and angiogenesis in vivo as well as migration and tube formation of endothelial cells in vitro. Noteworthy, the latter effect was enhanced after coapplication of cisplatin in nontoxic doses. An inhibitory effect on tumor cell migration was also observed suggesting a direct antitumor effect. Although thalidomide alone did not influence cell proliferation, it augmented antiproliferative response after cisplatin application emphasizing the idea of a potentiated effect when both drugs are combined. Furthermore, we could show that antiangiogenic effects of thalidomide are related to tumor-cell derived factors including vascular endothelial growth factor, basic fibroblast growth factor, hepatocyte growth factor and Il-8 some known and with, granulocyte colony stimulating growth factor and granulocyte macrophage colony stimulating growth factor, some new target molecules of thalidomide. Altogether, our findings reveal new insights into thalidomide-mediated antitumor and antiangiogenic effects and its interaction with cytostatic drugs.

An open-label phase II study of low-dose thalidomide in androgen-independent prostate cancer

The antiangiogenic effects of thalidomide have been assessed in clinical trials in patients with various solid and haematological malignancies. Thalidomide blocks the activity of angiogenic agents including bFGF, VEGF and IL-6. We undertook an open-label study using thalidomide 100 mg once daily for up to 6 months in 20 men with androgen-independent prostate cancer. The mean time of study was 109 days (median 107, range 4–184 days). Patients underwent regular measurement of prostate-specific antigen (PSA), urea and electrolytes, serum bFGF and VEGF. Three men (15%) showed a decline in serum PSA of at least 50%, sustained throughout treatment. Of 16 men treated for at least 2 months, six (37.5%) showed a fall in absolute PSA by a median of 48%. Increasing levels of serum bFGF and VEGF were associated with progressive disease; five of six men who demonstrated a fall in PSA also showed a decline in bFGF and VEGF levels, and three of four men with a rising PSA showed an increase in both growth factors. Adverse effects included constipation, morning drowsiness, dizziness and rash, and resulted in withdrawal from the study by three men. Evidence of peripheral sensory neuropathy was found in nine of 13 men before treatment. In the seven men who completed six months on thalidomide, subclinical evidence of peripheral neuropathy was found in four before treatment, but in all seven at repeat testing. The findings indicate that thalidomide may be an option for patients who have failed other forms of therapy, provided close follow-up is maintained for development of peripheral neuropathy.

Immunomodulatory analogs of thalidomide inhibit growth of Hs Sultan cells and angiogenesis in vivo.

We have previously shown that thalidomide and its potent immunomodulatory derivatives (IMiDs) inhibit the in vitro growth of multiple myeloma (MM) cell lines and patient MM cells that are resistant to conventional therapy. In this study, we further characterize the effect of these drugs on growth of B cell malignancies and angiogenesis. We established a beige-nude-xid (BNX) mouse model to allow for simultaneous in vivo measurement of both anti-tumor and anti-angiogenic effects of thalidomide and its analogs. Daily treatment (50 mg/kg/d) with thalidomide or IMiDs was nontoxic. The IMiDs were significantly more potent than thalidomide in vivo in suppressing tumor growth, evidenced by decreased tumor volume and prolonged survival, as well as mediating anti-angiogenic effects, as determined by decreased microvessel density. Our results therefore show that the IMiDs have more potent direct anti-tumor and anti-angiogenic effects than thalidomide in vivo, providing the framework for clinical protocols evaluating these agents in MM and other B cell neoplasms.

Novel therapies for multiple myeloma.

Novel therapies for multiple myeloma.

Effects of thalidomide, cytochrome P-450 and TNF-alpha on angiogenesis in a three-dimensional collagen gel-culture.

The anti-angiogenic effects of thalidomide were examined in mouse aortae grown in a three-dimensional collagen gel-culture. In our in vitro model, (+/-)-thalidomide and (-)-thalidomide exhibited no anti-angiogenic effects. On the other hand, when the culture was treated with thalidomide plus cytochrome P-450, both types of thalidomides significantly inhibited angiogenesis. Co-administration of 100 microg/ml thalidomide plus 200 microg/ml cytochrome P-450 inhibited angiogenesis more strongly than thalidomide plus cytochrome P-450 at other concentrations (10 microg/ml + 200 microg/ml and 100 microg/ml + 20 microg/ml). To study the relation between the anti-angiogenic effect and TNF-alpha, we also evaluated the concentration of TNF-alpha in the culture medium. We found that the concentration of TNF-alpha was correlated to the strength of the anti-angiogenic effect. The inhibition of angiogenesis by thalidomide and cytochrome P-450 takes place through a suppression of TNF-alpha and involves the metabolism of the thalidomide.

Effects of putative hydroxylated thalidomide metabolites on blood vessel density in the chorioallantoic membrane (CAM) assay and on tumor and endothelial cell proliferation.

Angiogenesis, in particular anti-angiogenesis, is an area of particular therapeutic interest in cancer treatment. Several anti-angiogenic agents are in the final stages of clinical trials. One of these agents, thalidomide, best known for its teratogenic potential, is showing promise against several tumor types. Thalidomide has been shown previously to require bio-activation to exert its anti-angiogenic effect in isolated blood vessels and endothelial cells. In this work, we confirmed these findings using the in utero chicken embryo chorioallantoic membrane (CAM) system. In particular, the anti-angiogenic effect of thalidomide is significantly enhanced by activation by human but not by rat liver microsomes. We also showed in the CAM assay that hydroxylation of thalidomide at either the 1'- or 5-position retained anti-angiogenic activity whereas its hydroxylation at the 4-position led to an inactive compound. We further demonstrated that thalidomide shows weak anti-proliferative activity against MDA-MB-231 human breast cancer cells in culture. Thalidomide showed slightly more anti-proliferative activity, however, against the SH-SY5Y human neuroblastoma and human umbilical vein endothelial cell (HUVEC) types. Furthermore, incubation of thalidomide with human liver microsomes added no additional anti-proliferative effect in these cell types versus thalidomide given alone. Finally, we report that none of the thalidomide metabolites tested had any anti-proliferative effect against the breast or neuroblastoma cells, but do possess appreciable anti-proliferative activity against the endothelial cells. In summary, this work suggests that hydroxylated thalidomide analogs based on putative metabolites of the drug possess significant anti-angiogenic activity and that exploring further derivatives of these as potential anti-angiogenic agents warrants further merit.

Thalidomide: new indications?

Thalidomide, which was developed as a nonbarbiturate sedative agent, was taken off the market in 1961 after it was linked to a spate of major birth defects. Gradually, thalidomide was reintroduced for the treatment of a few skin diseases including leprous erythema nodosum, severe mucosal ulcers (e.g., associated with HIV infection or Behçet’s disease), lymphocytic skin infiltrations, cutaneous lupus erythematosus, and chronic graft-versus-host disease. Recent reports of original pharmacological properties including modulation of cytokine production (mainly reduced TNF-α production) and inhibition of angiogenesis have led to the suggestion that thalidomide may be useful in some inflammatory and neoplastic conditions. Several open-label studies and case reports have described the effects of thalidomide in Crohn’s disease, rheumatoid arthritis, ankylosing spondylarthritis, systemic sclerosis, and a few other systemic disorders. In these indications, minor but dose-limiting side effects were apparently common. Thalidomide analogs with better acceptability profiles are under evaluation. The anti-angiogenic effects of thalidomide may make this compound valuable as single-drug therapy or as an adjunct to chemotherapy in patients with cancer, particularly those with metastases or multiple myeloma. This possibility requires further evaluation.

Inhibition of Angiogenesis by Thalidomide Requires Metabolic Activation, Which Is Species-dependent

Thalidomide has been shown to be an inhibitor of angiogenesis in a rabbit cornea micropocket model; however, it has failed to demonstrate this activity in other models. These results suggest that the anti-angiogenic effects of thalidomide may only be observed following metabolic activation of the compound. This activation process may be species specific, similar to the teratogenic properties associated with thalidomide. Using a rat aorta model and human aortic endothelial cells, we co-incubated thalidomide in the presence of either human, rabbit, or rat liver microsomes. These experiments demonstrated that thalidomide inhibited microvessel formation from rat aortas and slowed human aortic endothelial cell proliferation in the presence of human or rabbit microsomes, but not in the presence of rat microsomes. In the absence of microsomes, thalidomide had no effect on either microvessel formation or cell proliferation, thus demonstrating that a metabolite of thalidomide is responsible for its anti-angiogenic effects and that this metabolite can be formed in both humans and rabbits, but not in rodents.