Repurposing of the Drug Tezosentan for Cancer Therapy

Abstract

Tezosentan is a vasodilator drug that was originally developed to treat pulmonary arterial hypertension. It acts by inhibiting endothelin (ET) receptors, which are overexpressed in many types of cancer cells. Endothelin-1 (ET1) is a substance produced by the body that causes blood vessels to narrow. Tezosentan has affinity for both ET_A and ET_B receptors. By blocking the effects of ET1, tezosentan can help to dilate blood vessels, improve the blood flow, and reduce the workload on the heart. Tezosentan has been found to have anticancer properties due to its ability to target the ET receptors, which are involved in promoting cellular processes such as proliferation, survival, neovascularization, immune cell response, and drug resistance. This review intends to demonstrate the potential of this drug in the field of oncology. Drug repurposing can be an excellent way to improve the known profiles of first-line drugs and to solve several resistance problems of these same antineoplastic drugs.

Keywords: cancer; drug repurposing; endothelin receptors; tezosentan.

Figure 1

Chemical structure of the drug tezosentan (figure edited from DrugBank.com; accessed on 25 March 2023).

Figure 2

Actions of endothelin-1 in cancer.

Figure 3

The ET1 signaling network. ET1, a signaling molecule involved in cancer, activates several pathways that contribute to various cellular processes. Upon binding to its receptor, it initiates a cascade of events involving G-protein coupled receptor activation and the activation of primary effectors. One of the pathways activated by ET1 is through the activation of PLCβ. This enzyme cleaves a molecule called phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) into diacylglycerol (DAG) and inositol triphosphate (IP3). This leads to an increase in calcium levels and the activation of protein kinase C (PKC). Additionally, this pathway triggers the activation of members of the MAPK family, including ERK1/2, which are important for cellular signaling. ET1 activation also stimulates the Ras/Raf/MEK pathway, which converges on the activation of ERK1/2. This pathway plays a role in transmitting signals that regulate cell growth and proliferation. Furthermore, ET1 stimulation activates phospholipase A (PLA), resulting in the release of arachidonic acid (AA) and the activation of cyclooxygenase-1 (COX-1) and COX-2. These enzymes are involved in the production of prostaglandin E2 (PGE2). ET1 also activates PI3K, leading to the activation of AKT, integrin-linked kinase (ILK), and glycogen synthase kinase (GSK)-3β, which in turn stabilizes β-catenin. Importantly, ET1 can also activate ERK1/2 and PI3K/AKT/β-catenin signaling through the involvement of β-arrestin1. Through β-arrestin1, ET1 also activates nuclear factor-kB (NF-kB) signaling by inhibiting NF-kB inhibitor (IkB), leading to the dissociation and subsequent nuclear localization of active NF-kB. Additionally, ET1 activates PDZ-RhoGEF, leading to the activation of Rho-A and -C GTPases. This activation triggers Rho-dependent signaling events through RHO-associated coiled-coil containing protein kinase 1 (ROCK1), resulting in the activation of LIMK and the inhibition of cofilin. Collectively, these signaling pathways, orchestrated by ET-1R, promote cell growth, chemoresistance, angiogenesis, cytoskeleton remodeling, invadopodia formation, and metastasis. By understanding and targeting these pathways, it may be possible to develop therapeutic strategies to intervene in cancer progression.

Figure 4

Concentration-dependent effects of NO in cancer. When NO is present in low concentrations, it can improve the molecular processes that maintain normal physiology. However, in already established cancers, low levels of NO may promote cancer progression by enhancing processes such as proliferation and angiogenesis, and the switch to immunologically suppressive immune cell types. In contrast, high levels of NO can induce DNA damage, activate p53, and cause nitrosative stress. While this may promote the development of cancer initially, in already established cancers, high levels of NO can actually activate immunity and improve the effectiveness of chemotherapy. Overall, the effects of NO on cancer depend on the stage of the cancer and the concentration of NO present. While low levels of NO can enhance cancer progression, high levels of NO can induce DNA damage and activate immunity to improve chemotherapeutic efficacy.