Zoledronic acid reverses cisplatin resistance in nasopharyngeal carcinoma cells by activating the mitochondrial apoptotic pathway

You, Yanjie; Li, Haijun; Chen, Jiongyu; Xin, Qin; Ran, Yonggang

doi:10.3892/ol.2017.5611

Cited by 5 publications

(10 citation statements)

References 27 publications

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“…Radiotherapy and adjuvant chemotherapy have become the standard treatments for multiple types of cancer, including esophageal and nasopharyngeal carcinoma (1,2). Although radiotherapy is widely used to treat early-stage tumors, patients with advanced-stage tumors often experience failure of treatment mainly due to resistance to radiotherapy, resulting in recurrence and distant metastases (2)(3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Zoledronic acid augments the radiosensitivity of cancer cells through perturbing S- and M-phase cyclins and p21CIP1 expression

Wang

et al. 2017

Oncology Letters

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Abstract. Radiotherapy and adjuvant chemotherapy have become the standard treatments for multiple types of cancer. Although cancer cells are usually sensitive to radiotherapy, metastasis and local failure still occur mainly due to developed resistance to radiotherapy. Thus, it is critical to improve therapeutics for cancer treatment. The present study demonstrated that third-generation bisphosphonate zoledronic acid (ZOL), even at a low concentration, augments the radiosensitivity of cancer cells exposed to ionizing radiation (IR) by inducing S-phase arrest and subsequently promoting apoptosis. This function of ZOL was associated with elevated levels of cyclin A and cyclin B in the S and M phases, as well as decreased p21 CIP1 expression. In addition, ZOL also inhibited malignant the invasiveness of cancer cells. Notably, these effects could be enhanced concurrently with IR. The present data indicated that combined treatment with ZOL plus IR may be a novel technique to augment the radiosensitivity of cancer cells. IntroductionRadiotherapy and adjuvant chemotherapy have become the standard treatments for multiple types of cancer, including esophageal and nasopharyngeal carcinoma (1,2). Although radiotherapy is widely used to treat early-stage tumors, patients with advanced-stage tumors often experience failure of treatment mainly due to resistance to radiotherapy, resulting in recurrence and distant metastases (2-6). Therefore, the development of potent and reliable radiosensitizers is necessary for improving overall treatment outcomes in cancer therapy.Zoledronic acid (ZOL) is a compound containing nitrogen and bisphosphonates, which harbors anti-reabsorption effects (7). ZOL is used as therapy for bone metastasis in malignancy and a number of metabolic disorders, including bone pain, bone fractures and hypercalcaemia (8,9). ZOL inhibits farnesyl pyrophosphate synthase, a key enzyme in the isoprenoid biosynthetic pathway, and prevents prenylation of small guanosine triphosphate-binding proteins, including Rho, p21 ras , cell division cycle 42, Rac and Rab, which are essential for different cellular functions such as signal transduction and cell adhesion (7-9). ZOL is considered to possess antitumor activity, particularly in combination with chemotherapeutic anticancer drugs (10-12). This effect of ZOL could be observed on cancer cells derived from a variety of tumors, including breast, prostate and pancreatic cancers, by inducing cell apoptosis and inhibiting cell invasion, adhesion and angiogenesis (10-13). Currently, numerous patients with bone metastases secondary to a broad range of solid tumors are benefiting from the antitumor effects of ZOL (14).Our previous study demonstrated the synergistic cytotoxic effects of ZOL and ionizing radiation (IR) on esophageal squamous cell carcinoma and endothelial cells (15). Accordingly, combined treatment with ZOL plus IR may be an encouraging method to treat cancer with less side effects and complications, compared with the use of these agents alone (15)(16)(17)(18)(19...

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Section: Introductionmentioning

confidence: 99%

Zoledronic acid augments the radiosensitivity of cancer cells through perturbing S- and M-phase cyclins and p21CIP1 expression

Wang

et al. 2017

Oncology Letters

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“…Another study by Li et al further revealed that ZA inhibited HNE‐1 cells proliferation and induced apoptosis through inducing S‐phase cell cycle arrest and activating mitochondrial apoptotic pathway, as protein levels of anti‐apoptotic Bcl‐2 gene were downregulated and genes of Bax, Bad, and Caspase‐9 were upregulated . Addition to the direct anti‐proliferative effect on HNE‐1 cells, ZA exhibited another effect of reversing cisplatin resistance in a drug‐resistant sub‐cell line, HNE1/CDDP, by arresting cell cycle at S‐phase and inducing mitochondrial apoptotic pathway, similar with the mechanism of its anti‐proliferation on HNE‐1 cells. In our present study, we demonstrated ZA induced apoptosis in the poorly differentiated nasopharyngeal carcinoma CNE‐2Z cells via triggering ROS generation and subsequently activating ClC‐3 chloride channel, indicating another mechanism by which ZA exerts the anti‐cancer effect in nasopharyngeal carcinoma.…”

Section: Discussionmentioning

confidence: 97%

“…Zoledronic acid has shown its anti‐cancer effect in various types of carcinoma clinically . With regard to nasopharyngeal carcinoma, a subtype of head and neck cancers prevailing in Southeast Asia and Southeast China, ZA exerted its potential anti‐cancer effect in preclinical studies . Li et al demonstrated that ZA inhibited proliferation, migration and invasion of human nasopharyngeal carcinoma cell HNE‐1 via downregulating VEGF, MMP‐2, and MMP‐9 proteins expression .…”

Section: Discussionmentioning

confidence: 99%

The apoptotic effect of Zoledronic acid on the nasopharyngeal carcinoma cells via ROS mediated chloride channel activation

Wang

Gao

Xiao-ya

et al. 2018

Clin Exp Pharma Physio

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Zoledronic acid (ZA), a third-generation bisphosphonate, has been applied for treatment of bone metastases caused by malignant tumors. Recent studies have found its anti-cancer effects on various tumor cells. One of the mechanisms of anti-cancer effects of ZA is induction of apoptosis. However, the mechanisms of ZA-induced apoptosis in tumor cells have not been clarified clearly. In this study, we investigated the roles of chloride channels in ZA-induced apoptosis in nasopharyngeal carcinoma CNE-2Z cells. Apoptosis and chloride current were induced by ZA and suppressed by chloride channel blockers. After the knockdown of ClC-3 expression by ClC-3 siRNA, ZA-induced chloride current and apoptosis were significantly suppressed, indicating that the chloride channel participated in ZA-induced apoptosis may be ClC-3. When reactive oxygen species (ROS) generation was inhibited by the antioxidant N-acetyl-L-cysteine (L-NAC), ZA-induced apoptosis and chloride current were blocked accordingly, suggesting that ZA induces apoptosis through promoting ROS production and subsequently activating chloride channel.

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“…Our current study further supports that down-regulation of MLH1 increases resistance to cisplatin in vitro and in vivo. Clinically, some NPC patients are resistant to cisplatin-based chemotherapy (50,51), a phenomenon that is probably linked to a deficiency in MLH1, compromising the cisplatin-induced apoptotic signaling (52).…”

Section: Discussionmentioning

confidence: 99%

EBV infection is associated with histone bivalent switch modifications in squamous epithelial cells

Leong

Cheung

Dai

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Epstein−Barr virus (EBV) induces histone modifications to regulate signaling pathways involved in EBV-driven tumorigenesis. To date, the regulatory mechanisms involved are poorly understood. In this study, we show that EBV infection of epithelial cells is associated with aberrant histone modification; specifically, aberrant histone bivalent switches by reducing the transcriptional activation histone mark (H3K4me3) and enhancing the suppressive mark (H3K27me3) at the promoter regions of a panel of DNA damage repair members in immortalized nasopharyngeal epithelial (NPE) cells. Sixteen DNA damage repair family members in base excision repair (BER), homologous recombination, nonhomologous end-joining, and mismatch repair (MMR) pathways showed aberrant histone bivalent switches. Among this panel of DNA repair members,MLH1, involved in MMR, was significantly down-regulated in EBV-infected NPE cells through aberrant histone bivalent switches in a promoter hypermethylation-independent manner. Functionally, expression ofMLH1correlated closely with cisplatin sensitivity both in vitro and in vivo. Moreover, seven BER members with aberrant histone bivalent switches in the EBV-positive NPE cell lines were significantly enriched in pathway analysis in a promoter hypermethylation-independent manner. This observation is further validated by their down-regulation in EBV-infected NPE cells. The in vitro comet and apurinic/apyrimidinic site assays further confirmed that EBV-infected NPE cells showed reduced DNA damage repair responsiveness. These findings suggest the importance of EBV-associated aberrant histone bivalent switch in host cells in subsequent suppression of DNA damage repair genes in a methylation-independent manner.

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Zoledronic acid reverses cisplatin resistance in nasopharyngeal carcinoma cells by activating the mitochondrial apoptotic pathway

Cited by 5 publications

References 27 publications

Zoledronic acid augments the radiosensitivity of cancer cells through perturbing S- and M-phase cyclins and p21CIP1 expression

Zoledronic acid augments the radiosensitivity of cancer cells through perturbing S- and M-phase cyclins and p21CIP1 expression

The apoptotic effect of Zoledronic acid on the nasopharyngeal carcinoma cells via ROS mediated chloride channel activation

EBV infection is associated with histone bivalent switch modifications in squamous epithelial cells

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