Mcl-1 is an important therapeutic target for oral squamous cell carcinomas

Maji, Santanu; Samal, Sabindra K.; Pattanaik, Laxmipriya; Panda, Swagatika; Quinn, Bridget A.; Das, Swadesh K.; Sarkar, Devanand; Pellecchia, Maurizio; Fisher, Paul B.; Dash, Rupesh

doi:10.18632/oncotarget.3932

Cited by 51 publications

(39 citation statements)

References 42 publications

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“…After 4 weeks, tumor area was drawn and measured by the tool of freehand sections in the ImageJ software (National Institutes of Health). The details of the technical method were referred as previously described [20]. The decrease in tumor area in Nlrp3 −/− and Caspase1 −/− mice was compared with that of wild-type mice.…”

Section: Methodsmentioning

confidence: 99%

The role of NLRP3 inflammasome in 5-fluorouracil resistance of oral squamous cell carcinoma

Feng

Luo

Zhang

et al. 2017

J Exp Clin Cancer Res

128

103

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Background5-Fluorouracil (5-FU) is a widely used drug for the therapy of cancer. However, the chemoresistance of tumor cells to 5-FU usually limits its clinical effectiveness. In this study, we explored the role of NLRP3 inflammasome in 5-FU resistance of oral squamous cell carcinoma (OSCC).MethodsThe mRNA and protein expression levels of NLRP3, Caspase1 and IL-1β in resected OSCC specimens or cell lines were measured respectively by quantitative real time-PCR (qRT-PCR) and western blot. NLRP3 and Ki-67 expression in paraffin-embedded OSCC tissues was determined by immunohistochemistry. The correlation between 5-FU treatment and the expression and activation of NLRP3 inflammasome was further examined by evaluating NLRP3 and IL-1β expression in OSCC cell lines without or with NLRP3 knocked down. Cell viabilities of OSCC cells were determined by the MTT assay. Apoptosis and intracellular reactive oxygen species (ROS) of OSCC cells induced by 5-FU were measured by the flow cytometer. The carcinogen-induced tongue squamous carcinoma mice model was established by continuous oral administration of 4-nitroquinoline 1-oxide in wild-type BALB/c, Nlrp3 −/− and Caspase1 −/− mice. Tumor incidence were observed and tumor area were evaluated.ResultsIn the clinical analysis, expression and activation of NLRP3 inflammasome was clearly increased in OSCC tissues of patients who received 5-FU-based chemotherapy. Multivariate Cox regression analysis revealed that this high expression was significantly correlated with tumor stage and differentiation, and was associated with poor prognosis. Moreover, 5-FU treatment increased expression and activation of NLRP3 inflammasome in OSCC cells in a cell culture system and xenograft mouse model. Silencing of NLRP3 expression significantly inhibited OSCC cell proliferation and enhanced 5-FU-induced apoptosis of OSCC cells. Further investigation showed that intracellular ROS induced by 5-FU promoted the expression and activation of NLRP3 inflammasome and increased the production of interleukin (IL)-1β, which then mediated the chemoresistance. With the carcinogen-induced OSCC model, we found less and later tumor incidence in Nlrp3 −/− and Caspase1 −/− mice than wild-type mice. And greater decrease of tumor area was observed in the gene deficient mice treated with 5-FU.ConclusionsOur findings suggest that NLRP3 inflammasome promoted 5-FU resistance of OSCC both in vitro and in vivo, and targeting the ROS/NLRP3 inflammasome/IL-1β signaling pathway may help 5-FU-based adjuvant chemotherapy of OSCC.

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Section: Methodsmentioning

confidence: 99%

The role of NLRP3 inflammasome in 5-fluorouracil resistance of oral squamous cell carcinoma

Feng

Luo

Zhang

et al. 2017

J Exp Clin Cancer Res

128

103

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“…In human pancreatic carcinoma cell line BxPC‐3, 20 μM ApoG2 was also shown to diminish the interactions of MCL‐1‐BAX as well as BCL‐2‐BIM, all of which are correlated with apoptotic response . Apogossypol derivative, sabutoclax, a BCL‐XL, BCL‐2, and MCL‐1 inhibitor, have shown increased NOXA expression in H357, SCC‐4, SCC‐9 oral squamous cell carcinoma cell lines and FaDU human pharynx squamous cell carcinoma cell line at a concentration range between 1 and 2 μM . Another apogossypol derivative and a pan BCL‐2 family inhibitor that is also capable of targeting MCL‐1 was (–)BI97D6 .…”

Section: Mcl‐1 Inhibitorsmentioning

confidence: 95%

Selective targeting of antiapoptotic BCL‐2 proteins in cancer

Timuçin

Başağa

Kütük

2018

Medicinal Research Reviews

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Circumvention of apoptotic machinery is one of the distinctive properties of carcinogenesis. Extensively established key effectors of such apoptotic bypass mechanisms, the antiapoptotic BCL-2 (apoptosis regulator BCL-2) proteins, determine the response of cancer cells to chemotherapeutics. Within this background, research and development of antiapoptotic BCL-2 inhibitors were considered to have a tremendous amount of potential toward the discovery of novel pharmacological modulators in cancer. In this review, milestone achievements in the development of selective antiapoptotic BCL-2 proteins inhibitors for BCL-2, BCL-XL (BCL-2-like protein 1), and MCL-1 (induced myeloid leukemia cell differentiation protein MCL-1) were summarized and their future implications were discussed. In the first section, the design and development of BCL-2/BCL-XL dual inhibitor navitoclax, as well as the recent advances and clinical experience with selective BCL-2 inhibitor venetoclax, were synopsized. Preclinical data from selective BCL-XL inhibitors, which are currently undergoing extensive testing as a single agent or in combination with other therapeutic agents, were further summarized. In the second section, MCL-1 inhibitors developed as potential anticancer agents were reviewed regarding their specificity toward MCL-1. Explicitly, studies leading to the identification of MCL-1, nonselective and selective targeting of MCL-1, and recently initiated clinical trials were compiled in chronological order. Based on these concepts, future directions were further discussed for increasing selectivity in the design of prosurvival BCL-2 member inhibitors.

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“…7 Apoptosis is regulated in part by the Bcl-2 family members that consist of both proapoptotic and antiapoptotic proteins. 36 Among all the antiapoptotic Bcl-2 family members, Mcl-1 functions as a major survival factor, particularly in solid cancers, 37,38 and has emerged as a potential and promising target for cancer therapy. 39 Kang et al 40 Studies had discovered that PEITC was able to enhance the cytotoxic effects with other chemotherapeutic drugs, 43 including platinum, 20,44 paclitaxel, 25,26 gemcitabine, 45,46 and etoposide.…”

Section: Discussionmentioning

confidence: 99%

Phenethyl isothiocyanate synergistically induces apoptosis with Gefitinib in non–small cell lung cancer cells via endoplasmic reticulum stress‐mediated degradation of Mcl‐1

Zhang

Chen

Cao

et al. 2020

Molecular Carcinogenesis

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Isothiocyanates (ITCs) are natural compounds abundant in cruciferous vegetables.Numerous studies have shown that ITCs exhibit anticancer activity by affecting multiple pathways including apoptosis and oxidative stress, and are expected to be developed into novel anticancer drugs. In our previous studies, we demonstrated that ITCs effectively inhibit the proliferation of non-small cell lung cancer (NSCLC) cells, also induce apoptosis and autophagy. In the present study, we found that phenethyl isothiocyanate (PEITC) had significant synergistic effects with epidermal growth factor receptor tyrosine kinase inhibitor Gefitinib in NSCLC cell lines NCI-H1299 and SK-MES-1; and the degradation of antiapoptotic factor myeloid cell leukemia 1 (Mcl-1) caused by PEITC treatment played key roles in the sensitivity of NSCLC cells to Gefitinib. We further illustrated that PEITC regulated the expression of Mcl-1 through protein kinase RNA-like endoplasmic reticulum kinase (PERK)-eukaryotic translation initiation factor 2α-CHOP-Noxa pathway by a posttranscriptional modulation. Pretreatment with endoplasmic reticulum stress (ER stress) inhibitor tauroursodeoxycholic acid and knockdown of PERK expression attenuated the degradation of Mcl-1 caused by PEITC. In in vivo study, nude mice bearing NCI-H1299 xenograft were administrated with PEITC (50 mg/kg, ip) and Gefitinib (50 mg/kg, ig) for 15 days, the PEITC-Gefitinib combination treatment resulted in a significant synergistic reduction in tumor growth, and significantly induced both ER stress and Mcl-1 degradation in tumor tissues. In conclusion, we explored the prospect of PEITC in improving the efficacy of targeted drug therapy and demonstrated the synergistic effects and underlined mechanisms of PEITC combined with Gefitinib in NSCLC cells treatment. This study provided useful information for developing novel therapy strategies by combination treatment of PEITC with targeted drugs. K E Y W O R D S Gefitinib, Mcl-1, non-small cell lung cancer, phenethyl isothiocyanate, synergistic effect | ZHANG ET AL.

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Mcl-1 is an important therapeutic target for oral squamous cell carcinomas

Cited by 51 publications

References 42 publications

The role of NLRP3 inflammasome in 5-fluorouracil resistance of oral squamous cell carcinoma

The role of NLRP3 inflammasome in 5-fluorouracil resistance of oral squamous cell carcinoma

Selective targeting of antiapoptotic BCL‐2 proteins in cancer

Phenethyl isothiocyanate synergistically induces apoptosis with Gefitinib in non–small cell lung cancer cells via endoplasmic reticulum stress‐mediated degradation of Mcl‐1

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