The role of cancer chemotherapeutic agents in the treatment of pulmonary arterial hypertension
Ibrahim, Yasmine Farouk Abd Elnasser
Suzuki, Yuichiro Justin
ABSTRACTPulmonary arterial hypertension (PAH) is a fatal disease without a cure. It is a progressive disease, and at the time of diagnosis, the pulmonary arterial walls have often thickened as a result of complex pathologic process. Increased resistance in the pulmonary circulation strains the right ventricle (RV), leading to right-sided heart failure and eventual death. Three classes of therapeutic agents have been approved for the treatment of PAH. However, though these agents can increase the quality of patient's lives, their influence on survival may be minimal. The primary function of these approved drugs is to promote vasodilation. However, the growth of vascular cells is also critical to the pathogenesis of PAH. Thus, agents that affect the remodeled vessels by killing unwanted cells should improve treatment strategies. One of the goals of this thesis was to evaluate the efficacy of different cancer chemotherapeutic agents to reverse the established pulmonary vascular remodeling in animal models of PAH. This work used three different groups of highly effective anti-tumor agents: anthracycline (daunorubicin), proteasome inhibitors (bortezomib and MG-132), and microtubule inhibitors (docetaxel). These agents mediate smooth muscle cell (SMC) death by different mechanisms. These studies were done to investigate the mechanism used by the anti-cancer agents to mediate the reversal of the pulmonary vascular pathology. In addition, this work explored the mechanisms leading to differential responses to this pharmacological treatment between the PAH rats and the normoxic controls. Additionally, this study was done to determine the efficacy of the tested drugs in reversing the altered hemodynamics and right ventricular hypertrophy in PAH rats.To accomplish the aims of this thesis, the chronic hypoxia model of pulmonary hypertension (PH) in rats that has been well utilized for the study of pulmonary vascular remodeling was used. Also, the recently developed SUGEN/hypoxia model of PH that exhibits pathologic features similar to human PAH was utilized.The results demonstrate that the administration of anti-tumor agents in rats with PH reduces the pulmonary vascular wall thickness of the media and the intima within 1-6 days. The death of pulmonary vascular cells and the reduction of pulmonary vascular wall thickness only occurred in the pulmonary arteries of animals with PH, and not in the vessels of normal, control animals. While daunorubicin achieved reversal of the thickening of pulmonary arterioles in the chronic hypoxia model, proteasome inhibitors and docetaxel corrected a more aggressive vascular pathology in the SUGEN/hypoxia model. Moreover, the results showed no obvious evidence for cardiotoxicity in PAH rats injected with the different anti-tumor agents.Further the thesis investigated two critical biological processes that control the cell fate between survival and death: apoptosis and autophagy. Through both in vivo and in vitro evidence, the data showed that the mechanism of the DNR-induced regression involves the promotion of apoptotic and autophagic cell death. The autophagic cell death was mainly meditated by LC3BII and seems to occur by a Beclin-1 independent mechanism. It was identified that the differential susceptibility to autophagic cell death is due to by Parkin serving as a survival factor in normal vessels.Docetaxel showed a different characteristic. The results revealed the inhibition of the autophagic cascade as a novel target for docetaxel-induced cell death. Autophagic inhibition is indicated by proteasome-mediated beclin-1 degradation and further by an accumulation of p62. The studies identified myosin-9 as an interesting molecule that interacts with beclin-1 in the initial autophagy signal and that enhances docetaxel's cell killing efficacy.Finally, this work established the concept that anti-tumor drugs capable of reducing pulmonary vascular wall thickness increase the efficacy of vasodilators to reduce elevated RVSP. Moreover, using docetaxel alone, on a different schedule of administration, resulted in reversal of the hemodynamic parameters and the associated right ventricular hypertrophy.Together, these studies provide three insights.1) Evidence that different cancer chemotherapeutic agents can be effective treatments to reverse the complex pulmonary vascular remodeling that is typical in the reported pathology in PAH patients.2) Novel findings for the mechanism of action of the clinically approved, anti-tumor agents; daunorubicin and docetaxel. Daunorubicin has been shown to use autophagic cell death to mediate pulmonary smooth muscle cell killing. On the contrary, docetaxel arrests the autophagy survival signal and further stresses the cell by accumulating the cellular autophagosomes.3) Potential promise in using different anti-tumor agents, solely and/or in combination with the currently used vasodilators for treating patients with PAH, who have often already developed pulmonary vascular remodeling at the time of diagnosis.
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