Cepharanthin-enhanced radiosensitivity through the inhibition of radiation-induced nuclear factor-κB activity in human oral squamous cell carcinoma cells

Abstract

We have already demonstrated that human head and neck cancer cells have significantly enhanced levels of transcription factor nuclear factor (NF)-κB activity compared to their normal counterparts, suggesting that NF-κB plays an important role in the development of head and neck cancer. However, it has been reported that chemotherapeutic agents and radiation activate NF-κB activity in cancer cells, thus making the cells radioresistant and chemoresistant. In addition, we have shown that the suppression of NF-κB activity enhanced apoptosis in oral squamous cell carcinoma cells. In this study, we examined whether cepharanthin-induced inhibition of NF-κB activity enhances radiosensitivity in human oral carcinoma cells. Cepharanthin is a biscoclaurine alkaloid extracted from the roots of Stephania cepharantha hayata, and is widely used in Japan for the treatment of patients with leucopenia, nasal allergy, and venomous snakebites. γirradiation (IR) induces NF-κB activity in oral carcinoma cells through the activation of upstream molecules, including Akt and IκB kinase. However, a luciferase assay revealed that cepharanthin suppresses IR-induced NF-κB activity in oral squamous cell carcinoma cells, thereby enhancing the radio-sensitivity. Western blot analysis showed an enhanced cleavage of poly-(ADP-ribose) polymerase protein in carcinoma cells by both cepharanthin treatment and IR exposure compared to IR or cepharanthin alone. In an in vivo study, B88 cells were s.c. inoculated into the backs of nude mice. Tumor-bearing nude mice received either cepharanthin, IR alone, or a combination of cepharanthin and IR. The combined treatment suppressed tumor growth significantly more than either cepharanthin or IR alone. Cepharanthin inhibited the production of IR-induced IL-6 and IL-8, which are downstream targets of NF-κB. In quantitative real-time RT-PCR, IR also induced the expression of anti-apoptotic proteins [cellular inhibitor of apoptosis protein (cIAP)-1 and-2] in carcinoma cells. Treatment of cancer cells with cepharanthin combined with exposure to IR decreased cIAP-1 and-2 mRNA expression. These findings suggested that the combination of radiotherapy and cepharanthin could enhance radiosensitivity in the treatment of human oral cancer.

Furano-sesquiterpene from soft coral, Sinularia kavarittiensis: induces apoptosis via the mitochondrial-mediated caspase-dependent pathway in THP-1, leukemia cell line

“…The understanding of apoptosis process has provided the basis for novel, targeted therapies that specifically induce cell death in carcinoma cell lines or enhance the cytotoxic effects of established chemotherapeutic agents in these cells [29]. Ability to manipulate the machinery of cell death is an obvious goal of medical research and effect on regulation of apoptosis might lead to new possibilities for cancer treatment [30]. It is well documented that the secondary metabolites of Sinularia sps have induced apoptotic DNA fragmentation and condensation of chromatin in A431 cells [31].…”

Inhibition of the STAT3 signaling pathway is involved in the antitumor activity of cepharanthine in SaOS2 cells

“…The inflammatory pathways that are important in carcinogenesis include NF-κB, STATs and COX -, and they are promising targets for cancer therapy [31,32] . Previous studies have shown that inactivation of NF-κB is an important mechanism for the antitumor activity of CEP [8,15,16] . SaOS2 is an osteosarcoma cell line in which STAT3 is constitutively activated and plays a crucial role in cell proliferation and survival [10,22,33] .…”

“…Although accumulating evidence has shown that CEP plays a potential role in inhibiting cell growth and inducing apoptosis in many tumors [3] , the underlying mechanism remains elusive. Because CEP is primarily an anti-inflammatory agent, the antitumor activity of CEP is associated with inhibition of inflammation-related signaling pathways, among which NF-κB inactivation is important [8,15,16] . In addition to NF-κB, the signal transducer and activator of transcription protein 3 (STAT3) is another critical inflammatory mediator that links inflammation and cancer [17] .…”

Remarkable enhancement of cytotoxicity of onconase and cepharanthine when used in combination on various tumor cell lines

“…39 It was recently reported that Cep sensitizes human oral carcinoma cells to radiation by inhibiting activation of NFκB. 55 As mentioned, the NFκB is the most likely target of Onc as well. 28 In analogy to Cep Onc also shows antioxidant properties.…”