Treatment of metastatic cervical cancer: Future directions involving targeted agents

Díaz-Padilla, Iván; Monk, Bradley J.; Mackay, Helen; Oaknin, Ana

doi:10.1016/j.critrevonc.2012.07.006

Cited by 70 publications

(55 citation statements)

References 99 publications

(94 reference statements)

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“…Cervical cancer is a key factor associated with morbidity and mortality in women worldwide (1). Infection with human papilloma viruses (HPV) triggers carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Exposure to TNF-α combined with TGF-β induces carcinogenesis in vitro via NF-κB/Twist axis

et al. 2017

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Abstract. Persistent human papilloma virus (HPV) infection induces chronic inflammation resulting in human cervical cancer. However, the mechanisms underlying carcinogenesis via chronic inflammation remain largely unclear. We investigated the role of pro-inflammatory factors in epithelial-mesenchymal transition (EMT) and cancer stem cell-like (CSCL) characteristics of HeLa cells exposed to TNF-α with or without TGF-β. We then determined the role of NF-κB/Twist signal axis in the pathogenesis of cervical cancer. We found that HeLa cells exposed to TNF-α following chronic treatment with TGF-β exhibited EMT, self-renewal and high mobility. Knockdown of NF-κBp65 inhibited NF-κB and Twist1 expression, and EMT and CSCL properties of HeLa cells following co-treatment with TNF-α and TGF-β. Conversely, overexpression of NF-κBp65 potentiated the above effects. However, knockdown or overexpression of Twist1 had no effect on NF-κBp65 expression, but inhibited or promoted EMT and CSCL features. Notably, overexpression of Twist1 rescued NF-κBp65 knockdown. Our results demonstrate the role of NF-κB/Twist signaling axis in which HeLa cells treated with TNF-α following chronic exposure to TGF-β induce EMT and CSCL properties. The NF-κB/Twist signal axis may represent an effective therapeutic target in cervical cancer. IntroductionCervical cancer is a key factor associated with morbidity and mortality in women worldwide (1). Infection with human papilloma viruses (HPV) triggers carcinogenesis. Most of the precancerous lesions do not progress to invasive carcinoma, suggesting that HPV is not the only factor contributing to the development of cervical cancer (2,3). However, persistent HPV infection alters the pro-inflammatory cytokine profile, resulting in chronic inflammation and recurrence of cervical cancer (4). Cancer stem cells (CSCs) play a vital role in cancer initiation and metastasis (5). Metastasis results in treatment failure and death (6). Epithelial-mesenchymal transition (EMT) has been implicated as the key factor in CSCs transformation (7,8). EMT has been shown to induce reversion to a CSC-like phenotype, linking CSCs and EMT (9,10).NF-κB is a classic transcription factor activated by inflammatory stimuli, such as LPS (11), TNF-α (12) and IL-10 (13). Activated NF-κB induces extensive gene expression in immune response (TNF-α), angiogenesis (VEGF), invasion (MMP-9) and EMT (Twist) (14-17). Furthermore, NF-κB, a pleiotropic transcription factor, has been implicated in . In mammary epithelial cells, EMT is upregulated via overexpression of NF-κBp65 (17).The transcriptional factor TWIST mediates EMT and cancer metastasis (18,19). In uterine cancers, Twist overexpression promotes invasion and metastasis (20-23). However, the role of NF-κB/Twist axis in cervical cancer has not been investigated. In this study, we focused on the role of NF-κB/ Twist axis in vitro, by co-treatment of human cervical cancer cell line HeLa with TNF-α and TGF-β. Materials and methodsReagents. DMEM was obtained from Gibco, FBS from PAA, trypsin a...

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“…Cervical cancer is a key factor associated with morbidity and mortality in women worldwide (1). Infection with human papilloma viruses (HPV) triggers carcinogenesis.…”

Section: Introductionmentioning

confidence: 99%

Exposure to TNF-α combined with TGF-β induces carcinogenesis in vitro via NF-κB/Twist axis

et al. 2017

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“…10 Diallyl disulfide (DADS; ie, CH2DCH-CH2-S-S-CH2-CHDCH2), an oil-soluble compound extracted from garlic (Allium sativum L.) documents as a potent compound to prevent cancer, genotoxicity, nephrotoxicity, and hepatotoxicity. 11,12 Although DADS has been reported to provide the anticancer activity in several cancer types by inhibiting cell cycle arrest and inducing apoptosis, 13,14 the molecular effect of DADS on high-LET carbon beams -regulated proliferation, cell cycle arrest and cell death is currently unknown.…”

Section: Introductionmentioning

confidence: 99%

Diallyl disulfide enhances carbon ion beams–induced apoptotic cell death in cervical cancer cells through regulating Tap73 /ΔNp73

Chen

Sun

et al. 2015

Cell Cycle

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Diallyl disulfide (DADS), extracted from crushed garlic by steam-distillation, has been reported to provide the anticancer activity in several cancer types. However, the effect of DADS on high-LET carbon beams -induced cell death remains unknown. Therefore, we used human cervical cancer cells to elucidate the molecular effects of this dallyl sulfide. Radiotherapy remains the mainstay of treatment, especially in advanced cervical cancer and there is still space to improve the radiosensitivity to reduce radiation dosage. In this study, we found that radiation effects evoked by high-LET carbon beam was marked by inhibition of cell viability, cell cycle arrest, significant rise of apoptotic cells, regulation of transcription factor, such as p73, as well as alterations of crucial mediator of the apoptosis pathway. We further demonstrated that pretreatment of 10 mM DADS in HeLa cells exposed to radiation resulted in decrease in cell viability and increased radiosensitivity. Additionally, cells pretreated with DADS obviously inhibited the radiationinduced G2/M phase arrest, but promoted radiation-induced apoptosis. Moreover, combination DADS and the radiation exacerbated the activation of apoptosis pathways through up-regulated ration of pro-apoptotic Tap73 to antiapoptotic DNp73, and its downstream proteins, such as FASLG, and APAF1. Taken together, these results suggest that DADS is a potential candidate as radio sensitive agent for cervical cancer.

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“…Despite advances in screening, vaccination and treatment of early stage disease, a proportion of patients will be diagnosed with advanced stage (stage IVB), recurrent or persistent cervical cancer. Specifically, patients with International Federation of Obstetrics and Gynecology (FIGO) stage IB-IIA disease have a recurrence risk ranging from 10% to 20% despite primary chemo-radiation, while those patients diagnosed FIGO stage IIB-IVA have a 50% to 70% chance of disease recurrence [3]. For this subset of patients, systemic chemotherapy remains the standard treatment.…”

Section: Introductionmentioning

confidence: 99%

Beyond angiogenesis blockade: targeted therapy for advanced cervical cancer

Eskander

Tewari

2014

J Gynecol Oncol

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The global burden of advanced stage cervical cancer remains significant, particular in resource poor countries where effective screening programs are absent. Unfortunately, a proportion of patients will be diagnosed with advanced stage disease, and may suffer from persistent or recurrent disease despite treatment with combination chemotherapy and radiation. Patients with recurrent disease have a poor salvage rate, with an expected 5-year survival of less than 10%. Recently, significant gains have been made in the antiangiogenic arena; nonetheless the need to develop effective alternate targeted strategies is implicit. As such, a review of molecular targeted therapy in the treatment of this disease is warranted. In an era of biologics, combined therapy with cytotoxic drugs and molecular targeted agents, represents an exciting arena yet to be fully explored.

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Treatment of metastatic cervical cancer: Future directions involving targeted agents

Cited by 70 publications

References 99 publications

Exposure to TNF-α combined with TGF-β induces carcinogenesis in vitro via NF-κB/Twist axis

Exposure to TNF-α combined with TGF-β induces carcinogenesis in vitro via NF-κB/Twist axis

Diallyl disulfide enhances carbon ion beams–induced apoptotic cell death in cervical cancer cells through regulating Tap73 /ΔNp73

Beyond angiogenesis blockade: targeted therapy for advanced cervical cancer

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