Astemizole-based anticancer therapy for hepatocellular carcinoma (HCC), and Eag1 channels as potential early-stage markers of HCC

Chávez-López, María de Guadalupe; Pérez‐Carreón, Julio Isael; Zúñiga-García, Violeta; Díaz-Chávez, José; Herrera, Luis A.; Caro-Sánchez, Claudia Haydeé Saraí; Acuña-Macías, Isabel; Gariglio, Patricio; Hernández-Gallegos, Elizabeth; Chiliquinga, Andrea Jazmín; Camacho, Javier

doi:10.1007/s13277-015-3299-0

Cited by 37 publications

(42 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…K Ca 3.1 could maintain the hyperpolarized membrane potential in cancer liver cells, which promotes Ca 2+ influx and facilitation of mitogenic activation [ 166 ]. Astemizole, a nonspecific inhibitor of K v 10.1 and K v 11.1 potassium channels, significantly decreased cell proliferation and increased apoptosis in vitro in the liver cancer cell lines HepG2 and HuH7 [ 167 ]. In the same study, the authors observed that astemizole clearly prevented HCC development in vivo .…”

Section: Cancermentioning

confidence: 99%

Ion Channels and Oxidative Stress as a Potential Link for the Diagnosis or Treatment of Liver Diseases

Ramírez

Vázquez-Sánchez

Carrión-Robalino

et al. 2016

Oxidative Medicine and Cellular Longevity

Self Cite

View full text Add to dashboard Cite

Oxidative stress results from a disturbed balance between oxidation and antioxidant systems. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) may be either harmful or beneficial to the cells. Ion channels are transmembrane proteins that participate in a large variety of cellular functions and have been implicated in the development of a variety of diseases. A significant amount of the available drugs in the market targets ion channels. These proteins have sulfhydryl groups of cysteine and methionine residues in their structure that can be targeted by ROS and RNS altering channel function including gating and conducting properties, as well as the corresponding signaling pathways associated. The regulation of ion channels by ROS has been suggested to be associated with some pathological conditions including liver diseases. This review focuses on understanding the role and the potential association of ion channels and oxidative stress in liver diseases including fibrosis, alcoholic liver disease, and cancer. The potential association between ion channels and oxidative stress conditions could be used to develop new treatments for major liver diseases.

show abstract

Section: Cancermentioning

confidence: 99%

Ion Channels and Oxidative Stress as a Potential Link for the Diagnosis or Treatment of Liver Diseases

Ramírez

Vázquez-Sánchez

Carrión-Robalino

et al. 2016

Oxidative Medicine and Cellular Longevity

Self Cite

View full text Add to dashboard Cite

show abstract

“…For example, astemizole has shown anti-cancer activity for cervical cancer, hepatocellular carcinoma, melanoma and breast cancer43444546. These reports suggested that the mechanism associated with the anti-cancer activities of astemizole were due to its on-target (H1 receptor) and off-targets (Erg potassium channels), as the histamine receptors and potassium channels have been found to play important roles in tumor cell homeostasis47484950.…”

Section: Discussionmentioning

confidence: 99%

A structure- and chemical genomics-based approach for repositioning of drugs against VCP/p97 ATPase

Segura‐Cabrera

Tripathi

Zhang

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Valosin-containing protein (VCP/p97) ATPase (a.k.a. Cdc48) is a key member of the ER-associated protein degradation (ERAD) pathway. ERAD and VCP/p97 have been implicated in a multitude of human diseases, such as neurodegenerative diseases and cancer. Inhibition of VCP/p97 induces proteotoxic ER stress and cell death in cancer cells, making it an attractive target for cancer treatment. However, no drugs exist against this protein in the market. Repositioning of drugs towards new indications is an attractive alternative to the de novo drug development due to the potential for significantly shorter time to clinical translation. Here, we employed an integrative strategy for the repositioning of drugs as novel inhibitors of the VCP/p97 ATPase. We integrated structure-based virtual screening with the chemical genomics analysis of drug molecular signatures, and identified several candidate inhibitors of VCP/p97 ATPase. Importantly, experimental validation with cell-based and in vitro ATPase assays confirmed three (ebastine, astemizole and clotrimazole) out of seven tested candidates (~40% true hit rate) as direct inhibitors of VCP/p97 and ERAD. This study introduces an effective integrative strategy for drug repositioning, and identified new drugs against the VCP/p97/ERAD pathway in human diseases.

show abstract

“…Eag channels have also been detected in the normal retina [13,14]. In contrast, Eag1 is overexpressed in many cancer cell lines and human tumors, including those from the liver, cervix, lung, breast, and colon [11,13,[15][16][17][18][19]. Interestingly, the human Eag-related channel (Herg1), which is very relevant for cardiac repolarization [20], has been found to be overexpressed in retinoblastoma samples from patients that did not benefit from conservative treatment, namely chemotherapy followed by cryotherapy and/or laser treatment [21].…”

Section: Introductionmentioning

confidence: 99%

Eag1 Gene and Protein Expression in Human Retinoblastoma Tumors and its Regulation by pRb in HeLa Cells

Chávez-López

Zúñiga-García

Castro-Magdonel

et al. 2020

Genes

View full text Add to dashboard Cite

Retinoblastoma is the most common pediatric intraocular malignant tumor. Unfortunately, low cure rates and low life expectancy are observed in low-income countries. Thus, alternative therapies are needed for patients who do not respond to current treatments or those with advanced cases of the disease. Ether à-go-go-1 (Eag1) is a voltage-gated potassium channel involved in cancer. Eag1 expression is upregulated by the human papilloma virus (HPV) oncogene E7, suggesting that retinoblastoma protein (pRb) may regulate Eag1. Astemizole is an antihistamine that is suggested to be repurposed for cancer treatment; it targets proteins implicated in cancer, including histamine receptors, ATP binding cassette transporters, and Eag channels. Here, we investigated Eag1 regulation using pRb and Eag1 expression in human retinoblastoma. The effect of astemizole on the cell proliferation of primary human retinoblastoma cultures was also studied. HeLa cervical cancer cells (HPV-positive and expressing Eag1) were transfected with RB1. Eag1 mRNA expression was studied using qPCR, and protein expression was assessed using western blotting and immunochemistry. Cell proliferation was evaluated with an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. RB1 transfection down-regulated Eag1 mRNA and protein expression. The human retinoblastoma samples displayed heterogeneous Eag1 mRNA and protein expression. Astemizole decreased cell proliferation in primary retinoblastoma cultures. Our results suggest that Eag1 mRNA and protein expression was regulated by pRb in vitro, and that human retinoblastoma tissues had heterogeneous Eag1 mRNA and protein expression. Furthermore, our results propose that the multitarget drug astemizole may have clinical relevance in patients with retinoblastoma, for instance, in those who do not respond to current treatments.

show abstract

Astemizole-based anticancer therapy for hepatocellular carcinoma (HCC), and Eag1 channels as potential early-stage markers of HCC

Cited by 37 publications

References 35 publications

Ion Channels and Oxidative Stress as a Potential Link for the Diagnosis or Treatment of Liver Diseases

Ion Channels and Oxidative Stress as a Potential Link for the Diagnosis or Treatment of Liver Diseases

A structure- and chemical genomics-based approach for repositioning of drugs against VCP/p97 ATPase

Eag1 Gene and Protein Expression in Human Retinoblastoma Tumors and its Regulation by pRb in HeLa Cells

Contact Info

Product

Resources

About