Repurposing cimetidine for cholangiocarcinoma: Antitumor effects in vitro and in vivo

Abstract

Abstract. Cimetidine is a histamine type-2 (H 2 ) receptor antagonist that has been demonstrated to have antitumor effects on various types of malignancy. However, its effect on cholangiocarcinoma (CCA), a chemotherapy-resistant bile duct tumor, has yet to be investigated. In the present study, the antitumor activity of cimetidine in vitro and in vivo was evaluated. A methylthiotetrazole assay revealed that the proliferation of certain CCA cell lines was inhibited by cimetidine, which induced the caspase-dependent apoptosis of CCA cells via suppression of the protein kinase B signaling pathway. Suppression of Akt phosphorylation, caspase-3, -8 and -9 activation, phosphotidylserine exposure determined by Annexin V binding assay and the presence of a sub-G1 population were demonstrated by western blotting and flow cytometry analysis. In a CCA xenograft mouse model cimetidine inhibited the growth of CCA cells without observable adverse effects. These results suggest that cimetidine has the potential to be an effective antitumor agent for the treatment of CCA. IntroductionCholangiocarcinoma (CCA) is a highly lethal type of cancer that arises from the bile duct epithelium (1). Although CCA is a rare form of cancer, the global incidence of CCA is increasing, particularly that of the intrahepatic subtype (2). However, the highest incidence of CCA has been reported in the northeast of Thailand where the carcinogenic liver fluke Opisthorchis viverrini is considered a causative agent (3). The early diagnosis of CCA is challenging as patients with CCA typically have non-specific symptoms, and CCA tumor markers are yet to be developed (4). The majority of patients with CCA present with a late-stage disease that is frequently inoperable, and the outcomes of conventional chemotherapy or radiotherapy are unsatisfactory (5). Therefore, a unique approach to developing novel targeting therapies is required to reduce CCA-associated mortality.Cimetidine is an antagonist of histamine type-2 (H 2 ) receptors and is indicated for patients with gastro-esophageal reflux diseases, peptic ulcers or hypersecretory conditions (6,7). The effect of cimetidine on the survival of patients has been reported in various types of cancer, including gastric cancer (8), colorectal cancer (6,9,10), renal cell carcinoma (11), malignant melanoma (12) and glioblastoma (13). Numerous molecular mechanisms underlying the anticancer activities of cimetidine have been revealed, including the inhibition of cell proliferation by blocking the cell growth-promoting effect of histamine (14), the inhibition of tumor angiogenesis (15), the stimulation host immune responses (16) and the suppression of cell adhesion (17). However, the effects of cimetidine in CCA have yet to be demonstrated.In the present study, the anti-CCA activity of cimetidine was examined and the antiproliferative and apoptosis-inducing effects of cimetidine were determined. This was revealed to be partially due to the suppression of protein kinase B (Akt) phosphorylation. A CCA transplant xenogra...

Potential candidate treatment agents for targeting of cholangiocarcinoma identified by gene expression profile analysis

“…The results indicated that non-antineoplastic agents interacted with certain genes implicated in CCA. Cimetidine, a histamine type 2 antagonist, is used to treat heartburn and peptic ulcer; however, data also indicates that cimetidine may contribute to growth inhibition and apoptosis induction in CCA in vitro and in vivo ( 57 ). Valproic acid is used to treat bipolar disorders and prevent migraine headaches; previous study identified that it may inhibit the growth of CCA cell lines (TFK-1, QBC939 and CCLP1) by inducing cell cycle arrest and promoting cell differentiation via induction of dendrite-like structures ( 58 ).…”

The Akt pathway in oncology therapy and beyond (Review)

“…Recent research has demonstrated the potential of propofol, an intravenous anesthetic drug, to be repurposed to overcome resistance to imatinib in chronic myeloid leukemia treatment ( 123 ). Cimetidine, a drug used in the treatment of peptic ulcers, induces the apoptotic death of cholangiocarcinoma cells by the suppression of Akt phosphorylation and may be an effective candidate for future treatments ( 124 ). A well-known antifungal agent, itraconazole, has demonstrated anticancer activity in various cell lines by inhibiting Akt/mTOR signaling ( 125 ).…”

Involvement of histamine H1 and H2 receptor inverse agonists in receptor's crossregulation

“…In this sense, novel clinical applications for histamine H 1 receptor antagonists/inverse agonists are currently being studied for the management of different pathological situations, such as inflammatory-related conditions (in combination with glucocorticoids) (Zappia et al, 2015), analgesia (Stein et al, 2016) or neurodegenerative and sleep disorders (Kim and Song, 2017;Krystal, 2015). In the same way, evidence for anti-cancer effects of the histamine H 2 receptor inverse agonist cimetidine has been reported in various types of neoplasias, including glioblastoma, cholangiocarcinoma, malignant melanoma, renal cell carcinoma, colorectal and gastric cancer (Dana et al, 2017;Pantziarka et al, 2014).…”