The synergistic antitumor effect of cinobufagin and cisplatin in human osteosarcoma cell line in vitro and in vivo

Abstract

Cisplatin (CDDP) has been shown to be a promising anticancer drug that is effective against many types of cancer, which include osteosarcoma (OS). However, its therapeutic application is restricted by its toxicity in normal tissues and by side effects caused in patients. Reduction of the toxicity of CDDP is necessary to improve cancer treatment. In the present study, we attempted to clarify how cinobufagin, a traditional Chinese medicine, enhances CDDP-induced cytotoxicity in OS cells. OS 143B cells were treated with cinobufagin and CDDP alone or in combination. After low dose combined treatments with cinobufagin and CDDP, the effects of these therapeutics on cell proliferation, apoptosis, cell cycle, migration, invasion, and involvement in Notch pathway, as well as tumor growth and metastatic capability were determined. It was found that the combination of low doses of cinobufagin and CDDP markedly inhibited cell activity, motility, and induced apoptosis and cell cycle arrest in S phase, as well as suppressing tumor growth, metastasis and prolonging longer survival of nude mice in OS xenograft models compared with the actions of either drug alone or vehicle. The results also demonstrated that cinobufagin plus CDDP significantly suppressed the Notch pathway. The anticancer mechanism of these two drugs may involve intervention in the Notch signaling, which may contribute to inhibit tumor growth. All of these results suggest that application of lower concentration cinobufagin plus CDDP could produce a synergistic antitumor effect and this finding warrants further investigation for its potential clinical applications in human OS patients.

Network Pharmacology Prediction: The Possible Mechanisms of Cinobufotalin against Osteosarcoma

“…Compared with the effect of cisplatin alone, the combination of low-dose cisplatin significantly inhibits cell viability and motility, induces apoptosis and cell cycle arrest in the S phase, and inhibits tumor growth and metastasis, as well as prolongs the exposure of mice. Beside, longer survival time [ 17 ] in the OS xenograft model significantly inhibited the Notch signaling pathway. Gamabufotalin [ 18 ] inhibits the viability of osteosarcoma cells and tumorigenesis by blocking the TGF- β /periostin/PI3K/AKT signaling pathway.…”

Cinobufagin Induces Cell Cycle Arrest at the G2/M Phase and Promotes Apoptosis in Malignant Melanoma Cells

“…In recent years, a large number of studies have shown that the extract of Venenum Bufonis can inhibit the proliferation of some tumor cells (29). As one of the active components of Venenum Bufonis, cinobufagin has also entered garnered interest from researchers, as it has been reported that cinobufagin can effectively inhibit the proliferation of lung cancer cells (30), liver cancer cells (17), prostate cancer cells (31), and osteosarcoma cells (32) in vitro . In this study, we investigated the effects of cinobufagin on the proliferation of A375 human malignant melanoma cells and its intrinsic mechanism.…”

The spinal microglial IL-10/β-endorphin pathway accounts for cinobufagin-induced mechanical antiallodynia in bone cancer pain following activation of α7-nicotinic acetylcholine receptors

“…Gavage and intraperitoneal administration of Bufonis venenum, cinobufagin and bufalin produced marked antinociception in the hot-plate, formalin and acetic acid writing tests [74,81,82]. Interestingly, Bufonis venenum has remarkable analgesic effect in patients with cancer pain including that from bone metastasis [22,50], while it has been also served as an antitumor agent [2,12,25,48]. Preclinical studies showed that multiple daily intraperitoneal injections of Bufonis venenum (referred as to cinobufagin in the original paper) exerted mechanical antiallodynia and thermal antihyperalgesia in a mouse model of paw cancer pain [9,10].…”