Inhibition of HIF-1 activation for anti-tumor and anti-inflammatory responses
The presently disclosed subject matter generally relates to methods and compositions for inhibiting the expression and/or activation of hypoxia-inducible factor 1 (HIF-1) genes in a hypoxic cell. More particularly, the methods disclosed herein relate to inhibition of HIF-1 activation in a cell, increasing sensitivity of a tumor cell to radiation and/or chemotherapy, delaying tumor growth, inhibiting tumor blood vessel growth, inhibiting inflammatory responses in a cell through the use of compositions that prevent the nitrosylation of HIF-1, and methods for screening for new inhibitors of HIF-1 activiation. Additionally, the compositions disclosed herein relate to compositions that can be employed in, and are identified by, the disclosed methods.
1. A method for enhancing radiation therapy by inhibiting a macrophage-mediated stabilization of HIF-1 in a tumor undergoing radiation therapy free of cytotoxic chemotherapy, the method comprising:
(i) providing a radiation therapy free of cytotoxic chemotherapy by irradiating a tumor in a subject, wherein the radiation increases the number of tumor-associated macrophages, wherein the tumor-associated macrophages produce nitric oxide through inducible nitric oxide synthase, whereby the nitric oxide stabilizes HIF-1 in the irradiated tumor; and then
(ii) contacting the irradiated tumor having stabilized HIF-1 with a composition comprising a minimally therapeutic dose of an inhibitor of inducible nitric oxide synthase to inhibit HIF-1 stabilization, whereby the minimally therapeutic dose of an inhibitor of inducible nitric oxide synthase is sufficient to prevent production of nitric oxide through inducible nitric oxide synthase in tumor-associated macrophages for a number of days following irradiation,
whereby a macrophage-mediated stabilization of HIF-1 in the tumor is inhibited such that the radiation therapy is enhanced.
2. The method of claim 1 , wherein the subject is a mammal.
3. The method of claim 2 , wherein the mammal is a human.
4. The method of claim 1 , wherein the composition inhibits nitrosylation of Cys520 of SEQ ID NO: 6.
5. The method of claim 1 , wherein the nitric oxide produced by inducible nitric oxide synthase nitrosylates Cys520 of SEQ ID NO: 6, whereby the nitrosylation of Cys520 of SEQ ID NO: 6 stabilizes HIF-1 in the tumor.
6. The method of claim 1 , wherein the tumor is irradiated in step (i), and then after a period of time the tumor is contacted with the composition in step (ii).