Imiquimod activates p53-dependent apoptosis in a human basal cell carcinoma cell line

Huang, Shi; Chang, S. L.; Mu, Szu Wei; Jiang, Hsin Yi; Wang, Sin Ting; Kao, Jun Kai; Liu, Luxin; Wu, Chun Ying; Chen, Yi Ju; Shieh, Jeng-Jer

doi:10.1016/j.jdermsci.2015.12.011

Cited by 45 publications

(43 citation statements)

References 46 publications

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“…El-Khattouti et al hypothesized that ER stress pathways are mediated through TLR7 activation [21], however we could not detect any expression of TLR7 in our cell lines prior to or after imiquimod treatment. As previous studies have also reported TLR7 independent activation of apoptosis in imiquimod treated tumour cell lines [13, 15, 18, 19, 37], we suggest imiquimod induces ER stress via alternative mechanisms.…”

Section: Discussionsupporting

confidence: 72%

“…These findings reflect the high amounts of imiquimod required for the immunotherapy of superficial basal carcinoma in humans, with FDA guidelines suggesting topical application of 0.5–2 mg of imiquimod almost daily [42]. It has been suggested that apoptotic pathways in imiquimod treated tumour cells are activated as a result of ROS accumulation, which enhances ASK-1 stimulation of JNK and p38 apoptotic pathways [18, 21, 37, 43–45]. Imiquimod-induced ROS production may occur as a result of calcium induced deregulation of oxidative phosphorylation [21], and rapid accumulation is likely due to the elevated metabolic activity of tumour cells.…”

Section: Discussionmentioning

confidence: 73%

“…Although imiquimod is an agonist of TLR7, previous studies have shown that it can exert effects in tumour cells via TLR7-independent mechanisms [13, 18, 37, 38]. To determine whether this is the case in DFTD, we examined TLR7 expression in DFT1 and DFT2 cell lines.…”

Section: Resultsmentioning

confidence: 99%

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The Immunomodulatory Small Molecule Imiquimod Induces Apoptosis in Devil Facial Tumour Cell Lines

et al. 2016

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The survival of the Tasmanian devil (Sarcophilus harrisii) is threatened by devil facial tumour disease (DFTD). This transmissible cancer is usually fatal, and no successful treatments have been developed. In human studies, the small immunomodulatory molecule imiquimod is a successful immunotherapy, activating anti-tumour immunity via stimulation of toll-like receptor-7 (TLR7) signaling pathways. In addition, imiquimod is a potent inducer of apoptosis in human tumour cell lines via TLR7 independent mechanisms. Here we investigate the potential of imiquimod as a DFTD therapy through analysis of treated DFTD cell lines and Tasmanian devil fibroblasts. WST-8 proliferation assays and annexin V apoptosis assays were performed to monitor apoptosis, and changes to the expression of pro- and anti-apoptotic genes were analysed using qRT-PCR. Our results show that DFTD cell lines, but not Tasmanian devil fibroblasts, are sensitive to imiquimod-induced apoptosis in a time and concentration dependent manner. Induction of apoptosis was accompanied by down-regulation of the anti-apoptotic BCL2 and BCLXL genes, and up-regulation of the pro-apoptotic BIM gene. Continuous imiquimod treatment was required for these effects to occur. These results demonstrate that imiquimod can deregulate DFTD cell growth and survival in direct and targeted manner. In vivo, this may increase DFTD vulnerability to imiquimod-induced TLR7-mediated immune responses. Our findings have improved the current knowledge of imiquimod action in tumour cells for application to both DFTD and human cancer therapy.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 73%

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The Immunomodulatory Small Molecule Imiquimod Induces Apoptosis in Devil Facial Tumour Cell Lines

et al. 2016

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“…Further study revealed that expression of Bcl-2 was downregulated and cleavage of caspase-3, caspase-7 was upregulated in imiquimod-treated cells (Smits et al, 2010), suggesting that the apoptosis-inducing effects of imiquimod were involved in a caspase-dependent mitochondrial pathway. Futhermore, imiquimod induced reactive oxygen species production to stimulate ATM/ATR pathways and lead to p53-dependent apoptosis in the skin basal cell carcinoma cells (Huang et al, 2016). However, there were no available studies testifying that MYD88 pathway activates p53 expression.…”

Section: Anti-tumor Mechanismmentioning

confidence: 99%

Anti-tumor Activity of Toll-Like Receptor 7 Agonists

et al. 2017

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Toll-like receptors (TLRs) are a class of pattern recognition receptors that play a bridging role in innate immunity and adaptive immunity. The activated TLRs not only induce inflammatory responses, but also elicit the development of antigen specific immunity. TLR7, a member of TLR family, is an intracellular receptor expressed on the membrane of endosomes. TLR7 can be triggered not only by ssRNA during viral infections, but also by immune modifiers that share a similar structure to nucleosides. Its powerful immune stimulatory action can be potentially used in the anti-tumor therapy. This article reviewed the anti-tumor activity and mechanism of TLR7 agonists that are frequently applied in preclinical and clinical investigations, and mainly focused on small synthetic molecules, including imiquimod, resiquimod, gardiquimod, and 852A, etc.

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“…ADORA promotes PKA activity leading to the phosphorylation of GLI and the selection of the repressor form of GLI . Imiquimod has been shown to stimulate p53‐induced apoptosis through increased ROS production and stimulation of the ATM/ATR . However, this mechanism may not operate in BCCs carrying mutant p53.…”

Section: Interventionsmentioning

confidence: 99%

Basal cell carcinoma pathogenesis and therapy involving hedgehog signaling and beyond

Bakshi

Chaudhary

Rana

et al. 2017

Molecular Carcinogenesis

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Basal cell carcinoma (BCC) of the skin is driven by aberrant hedgehog signaling. Thus blocking this signaling pathway by small molecules such as vismodegib inhibits tumor growth. Primary cilium in the epidermal cells plays an integral role in the processing of hedgehog signaling-related proteins. Recent genomic studies point to the involvement of additional genetic mutations that might be associated with the development of BCCs, suggesting significance of other signaling pathways, such as WNT, NOTCH, mTOR, and Hippo, aside from hedgehog in the pathogenesis of this human neoplasm. Some of these pathways could be regulated by noncoding microRNA. Altered microRNA expression profile is recognized with the progression of these lesions. Stopping treatment with Smoothened (SMO) inhibitors often leads to tumor reoccurrence in the patients with basal cell nevus syndrome, who develop 10–100 of BCCs. In addition, the initial effectiveness of these SMO inhibitors is impaired due to the onset of mutations in the drug-binding domain of SMO. These data point to a need to develop strategies to overcome tumor recurrence and resistance and to enhance efficacy by developing novel single agent-based or multiple agents-based combinatorial approaches. Immunotherapy and photodynamic therapy could be additional successful approaches particularly if developed in combination with chemotherapy for inoperable and metastatic BCCs.

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Imiquimod activates p53-dependent apoptosis in a human basal cell carcinoma cell line

Cited by 45 publications

References 46 publications

The Immunomodulatory Small Molecule Imiquimod Induces Apoptosis in Devil Facial Tumour Cell Lines

The Immunomodulatory Small Molecule Imiquimod Induces Apoptosis in Devil Facial Tumour Cell Lines

Anti-tumor Activity of Toll-Like Receptor 7 Agonists

Basal cell carcinoma pathogenesis and therapy involving hedgehog signaling and beyond

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