Figure 1: A diagram of the eye. The retina, vitreoushumour, and choroid are found in the posterior segment.
Shannon J Kelly Kathleen Halasz Vijaykumar SutariyaDepartment of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL 33612, USA
*Corresponding author: Vijaykumar Sutariya, Department of Pharmaceutical sciences, College of Pharmacy, University of South Florida 12901 Bruce B Downs Blvd MDC 30 Tampa, FL 33612- 4749, USA, Tel: 813-974-1401; Fax: 813-974-9890; E-mail: firstname.lastname@example.org
Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are two of the leading causes of vision loss in people over the age of 40 in the United States . Each of these conditions affects the posterior segment of the eye, which consists of the retina, vitreoushumour, and choroid (Figure 1) . There are two types of AMD, dry and wet. Dry AMD results from long term choroidal ischemia, or a restriction of blood flow in the choroid of the eye . Wet AMD is caused by scarring and bleeding into the macular resulting from choroidal neovascularization (CNV) . Bleeding from new abnormal blood vessels in the vitreoushumour and retina indicates the development of DR . The role of inflammation in AMD has been confirmed by the presence of macrophages, lymphocytes, and other inflammatory cells in the choroid .
It has been well-documented that the inflammation and angiogenesis that are characteristic of AMD and DR are caused by an increased expression of vascular endothelial growth factor (VEGF) in the eye [7- 9]. The suppression of VEGF [10-12] and amelioration of the resulting angiogenesis  are the current therapeutic strategies for posterior segment ocular diseases. However, VEGF is far from the only factor which can lead to pathological angiogenesis. It has been reported that the hypoxia induced factor 1α (HIF-1α) induces the over expression of VEGF and other proangiogenic factors that play key roles in ocular conditions [14,15]. The inhibition of HIF-1α may therefore prove to be a suitable therapeutic target for posterior segment ocular diseases like AMD and DR.
Several drugs have been identified as HIF-1α inhibitors including ritonavir, doxorubicin, digoxin, and honokiol (Figure 2).
Figure 2: The molecular structures of the HIF-1α inhibitors (A) ritonavir, (B) doxorubicin, (C) digoxin, and (D) honokiol
Ritonavir (Figure 2a) is a well-documented HIV-1 protease inhibitor [16-18]. The antiangiogenic effects of ritonavir in the treatment of Kaposi sarcoma and head and neck carcinoma have since been reported [19,20]. Vadlapatla et al  reported a concentration-dependent decrease in VEGF secretion in ARPE-19 and D407 cells in the presence of ritonavir. This demonstrated that ritonavir inhibits HIF-1α mediated VEGF expression in retinal pigment epithelial (RPE) cells . The nontoxic nature of this treatment  indicates that ritonavir could serve as a promising treatment for angiogenesis in posterior segment ocular diseases.
Doxorubicin (DOX) (Figure 2b) is an anthracycline antibiotic that has been used in the treatment of various cancers, including leukemia, breast cancer, ovarian cancer, lymphomas, and glioblastomas [22,23]. More recently, it has been demonstrated that doxorubicin prevents the up regulation of many proangiogenic factors, including VEGF. Iwase et al.  reported that a 10µg intravitreal injection of DOX reduced CNV in mice. DOX does not actually reduce the amount of HIF-1 present at the therapeutic site. Instead, DOX acts by blocking the binding of HIF-1 to DNA. Thus, it follows that DOX could serve as a possible therapy for ocular conditions resulting from angiogenesis. However, a long elimination half-life and nonspecific cell cytotoxicity have made DOX treatments disadvantageous [23,24]. Iwase et al  noted the development of precipitation on the retinal surface, likely resulting from the poor aqueous solubility of DOX. Studies have shown that the encapsulation of DOX by polymeric nano particles can reduce the cytotoxicity of DOX treatments and deliver a sustained release of drug [22-24].
Digoxin (Figure 2c) is a digitalis derivative that is commonly used to treat heart arrhythmia, heart failure, and atrial fibrillation. It has recently been reported that digoxin has the ability to inhibit HIF-1α protein synthesis . Yoshida et al  reported that digoxin inhibits HIF-1α expression and reduces mRNA expression levels in mice. They further reported that a 100ng intravitreal injection of digoxin reduced retinal neovascularization in mice by 70% . This potency suggests that digoxin could serve as a viable treatment for a multitude of ocular diseases caused by neovascularization, including AMD and DR.
Honokiol (Figure 2d) is a phytochemical found in the bark and cones of Magnolia plants. Honokiol has been used in traditional oriental medicine for its many therapeutic effects, including anti-inflammatory and anticancer therapies . The anti-HIF  and anti-angiogenic  effects of honokiol have been described. Vavilala et al  found that treatment with 10µM honokiol produced a significant reduction of HIF-1α, HIF- 2α, HIF-1β, and VEGF in D407, HT29, HEK293, and ARPE-19 cell lines [28,29]. The group later published a comparison of the efficacy of honokiol on HIF suppression in ARPE-19 cells to that of doxorubicin and digoxin . They concluded that honokiol was the most effective and least toxic of these three drugs. These studies suggest that honokiol offers potential for the treatment of ocular conditions caused by HIF-1α - mediated angiogenic factors.
It is well known that that inflammation and angiogenesis that causes such ocular conditions as AMD and DR is caused by an excessive production of VEGF in the eye. Current treatment strategies aim at suppressing VEGF secretion. VEGF and many other factors responsible for pathological angiogenesis are mediated by the hypoxia induced factor HIF-1α. By inhibiting HIF-1α, the excretion of these other factors will be reduced in addition to VEGF. Ritonavir, doxorubicin, digoxin, and honokiol have exhibited the ability to inhibit HIF-1α, thereby reducing the secretion of these proangiogenic factors. These HIF-1α inhibitors show potential in the treatment of ocular neovascularization. A sustained release delivery system, such as nanoparticles or thermo reversible hydrogels, could prove advantageous for treatment by reducing the required frequency of injection . This is beneficial as the frequent intravitreal injections required for many current therapies can result in increased intraocular pressure, retinal detachment, and hemorrhaging. Based on the positive effects of HIF-1α inhibitors ritonavir, doxorubicin, digoxin, and honokiol, the potential of HIF-1α inhibitors in ocular therapy looks promising.
- National Institute of Health (2010) Prevalence of Adult Vision Impairment and Age-Related Eye Diseases in America, NIH, USA. [Ref.]
- Hirani A, Grover A, Lee YW, Pathak Y, Sutariya V (2013) Polymerbased Therapies for Posterior Segment Ocular Disease. J Biomol Res Ther 3: e122. [Ref.]
- Urdang L (2009) The Bantam Medical Dictionary, 6th Edition New York, Bantam Books. [Ref.]
- Wang Y, Wang VM, Chan C (2011) The role of anti-inflammatory agents in age related macular degeneration (AMD) treatment. Eye 25: 127-139. [Ref.]
- Wenick AS, Bressler NM (2012) Diabetic Macular Edema: Current and Emerging Therapies. Middle East Afr J Ophthalmol 19: 4-12. [Ref.]
- Chen M, Xu H (2012) Inflammation in Age Related Macular Degeneration – Implications for Therapy. In: Khatami M (Eds) Inflammatory Diseases-Immunopathology, Clinical and Pharmacological Bases. Rijeka Croatia: In Tech 129-150. [Ref.]
- Kovach JL, Schwartz SG, Flynn HW, Scott IU (2012) Anti-VEGF Treatment Strategies for Wet AMD. J Ophthalmol 2012: 786870. [Ref.]
- Park YG, Rhu HW, Kang S, Roh YJ (2012) New approach of antiVEGF agents for age-related macular degeneration. J Ophthalmol 2012: 637316. [Ref.]
- Ferrara N, Gerber H-P, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669-676. [Ref.]
- Villegas VM, Aranguren LA, Kovach JL, Schwartz SG, Flynn HW (2017) Current advances in the treatment of neovascularage-related macular degeneration. Expert Opinion on Drug Delivery 14: 273-282. [Ref.]
- Hirani A, Grover A, Lee YW, Pathak Y, Sutariya V (2016) Triamcinolone acetonide nanoparticles incorporated in thermoreversible gels for age-related macular degeneration. Pharm Dev Technol 21: 61-67. [Ref.]
- Ferrara N (2009) Vascular Endothelial Growth Factor. Arterioscler Thromb Vasc Biol 29:789-791. [Ref.]
- Ferrara N, Kerbel RS (2005) Angiogenesis as a therapeutic target. Nature 438: 967-974. [Ref.]
- Hu K, Babapoor-Farrokhran S, Rodrigues M, Deshpande M, Puchner B, et al. (2016) Hypoxia-inducible factor 1 upregulation of both VEGF and ANGPTL4 is required to promote the angiogenic phenotype in uveal melanoma. Oncotarget 7: 7816-7828. [Ref.]
- Forsythe JA, Jiang B, Iyer NV, Agani F, Leung SW, et al. (1996) Activation of Vascular Endothelial Growth Factor GeneTranscription by Hypoxia-Inducible Factor 1. Mol Cell Biol 16: 4604-4613. [Ref.]
- Markowitz M, Saag M, Powderly WG, Hurley AM, Hsu A, et al. (1995) A Preliminary Study of Ritonavir, An Inhibitor of HIV-1 Protease, To Treat Hiv-1 Infection. N Engl J Med 333: 1534-1539. [Ref.]
- Danner SA, Carr A, Leonard JM, Lehman LM, Gudiol F, et al. (1995) A Short-Term Study of The Safety, Pharmacokinetics, And Efficacy of Ritonavir, An Inhibitor Of HIV-1 Protease. N Engl J Med 333: 1528-1533. [Ref.]
- Cameron W, Heath-Chiozzi M, Danner S, Cohen C, Kravcik S, et al. (1998) Randomised placebo-controlled trial of ritonavir in advanced HIV-1 disease. Lancet 351: 543-549. [Ref.]
- Maggiorella L, Wen B, Frascogna V, Opolon P, Bourhis J, et al. (2005) Combined radiation sensitizing and anti-angiogenic effects of ionizing radiation and the protease inhibitor ritonavir in a head and neck carcinoma model. Anticancer Res 25: 4357-4362. [Ref.]
- Pati S, Pelser CB, Dufraine J, Bryant JL, Reitz Jr, et al. (2002) Antitumorigenic effects of HIV protease inhibitor ritonavir: inhibition of Kaposi sarcoma. Blood 99: 3771-3779. [Ref.]
- Vadlapatla RK, Vadlapudi AD, Pal D, Mukherji M, Mitra AK (2014) Ritonavir Inhibits HIF-1α-mediated VEGF Expression in Retinal Pigment Epithelial Cells in vitro. Eye (Lond) 28: 93-101. [Ref.]
- Geldenhuys W, Wehrung D, Groshev A, Hirani A, Sutariya V (2015) Brain-targeted delivery of doxorubicin using glutathione-coated nanoparticles for brain cancers. Pharm Dev Technol 20: 497-506. [Ref.]
- Khemani M, Sharon M, Sharon M (2012) pH Dependent Encapsulation of Doxorubicin in PLGA. Annals of Biological Research 3: 4414-4419. [Ref.]
- Iwase T, Fu J, Yoshida T, Muramatsu D, Miki A, et al. (2013) Sustained Delivery of a HIF-1 Antagonist for Ocular Neovascularization. J Control Release 172: 625-633. [Ref.]
- Zhang H, Qian DZ, Tan YS, Lee K, Gao P, et al. (2008) Digoxin and other cardiac glycosides inhibit HIF-1α synthesis and block tumor growth. Proc Natl Acad Sci USA 105: 19579-19586. [Ref.]
- Yoshida T, Zhang H, Iwase T, Shen J, Semenza GL, et al. (2010) Digoxin inhibits retinal ischemia-induced HIF-1 expression and ocular neovascularization. FASEB J 24: 1759-1967. [Ref.]
- Lee Y, Lee YM, Lee C, Jung JK, Han SB, et al. (2011) Therapeutic applications of compounds in the Magnolia family. Pharmacol Ther 130: 157-176. [Ref.]
- Vivalala DT, Ponnaluri VKC, Vadlapatla RK, Pal D, Mitra AK, et al. (2012) Honokiol inhibits HIF pathway and hypoxia-induced expression of histone lysinedemethylases. Biochem Biophys Res Commun 422: 369-374. [Ref.]
- Vavilala DT, Ponnaluri VKC, Kanjilal D, Mukherji M (2014) Evaluation of Anti-HIF and Anti-Angiogenic Properties of Honokiol for the Treatment of Ocular Neovascular Diseases. PLOS one 9: e113717. [Ref.]
- Vavilala DT, O’Bryhim BE, Ponnaluri VKC, White RS, Radel J, et al. (2013) Honokiol inhibits pathological retinal neovascularization inoxygen-induced retinopathy mouse model. Biochem Biophys Res Commun 438:697-702. [Ref.]
Download Provisional PDF Here
Article Type: Short Communication
Citation: Kelly SJ, Halasz K, Sutariya V (2017) HIF- 1α Inhibitors for the Treatment of Posterior Segment Ocular Diseases. Int J Nanomed Nanosurg 3(1): doi http://dx.doi.org/10.16966/2470-3206.120
Copyright: © 2017 Kelly SJ, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.