Mithramycin A Inhibits Myeloid Cell Leukemia-1 to Induce Apoptosis in Oral Squamous Cell Carcinomas and Tumor Xenograft through Activation of Bax and Oligomerization

Shin, Ji Ae; Jung, Ji Youn; Ryu, Mi Heon; Safe, Stephen; Cho, Sung Dae

doi:10.1124/mol.112.081364

Cited by 29 publications

(38 citation statements)

References 38 publications

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“…Though it shows potential to treat neurodegenerative diseases such as Huntington’s Disease [1], Alzheimer’s, and Parkinson’s, it has primarily been investigated as an anticancer drug. Mithramycin has been used clinically against testicular cancer [2] and leukemia [3], and preclinical studies have shown activity against glioma [4], pancreatic cancer [5], prostate cancer [6], oral squamous cell carcinoma [7], and lung and esophageal cancer [8]. Patients receiving mithramycin often develop hepatotoxicity [9]; various analogs have been developed in an attempt to curtail dose-limiting side effects [10–12].…”

Section: Introductionmentioning

confidence: 99%

Quantitative determination of mithramycin in human plasma by a novel, sensitive ultra-HPLC–MS/MS method for clinical pharmacokinetic application

Roth

Peer

Widemann

et al. 2014

Journal of Chromatography B

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Mithramycin is a neoplastic antibiotic synthesized by various Streptomyces bacteria. It is under investigation as a chemotherapeutic treatment for a wide variety of cancers. Ongoing and forthcoming clinical trials will require pharmacokinetic analysis of mithramycin in humans, both to see if target concentrations are achieved and to optimize dosing and correlate outcomes (response/toxicity) with pharmacokinetics. Two published methods for mithramycin quantitation exist, but both are immunoassays that lack current bioanalytical standards of selectivity and sensitivity. To provide an upgraded and more widely applicable assay, a UPLC-MS/MS method for quantitation of mithramycin in human plasma was developed. Solid phase extraction allowed for excellent recoveries (>90%) necessary for high throughput analyses on sensitive instrumentation. However, a ~55% reduction in analyte signal was observed as a result of plasma matrix effects. Mithramycin and the internal standard chromomycin were separated on a Waters Acquity BEH C18 column (2.1x50mm, 1.7um) and detected using electrospray ionization operated in the negative mode at mass transitions m/z 1083.5→268.9 and 1181.5→269.0, respectively, on an AB Sciex QTrap 5500. The assay range was 0.5–500 ng/mL and proved to be linear (r2>0.996), accurate (≤10% deviation), and precise (CV<15%). Mithramycin was stable in plasma at room temperature for 24 hours, as well as through three freeze-thaw cycles. This method was subsequently used to quantitate mithramycin plasma concentrations from patients enrolled on two clinical trials at the NCI.

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Section: Introductionmentioning

confidence: 99%

Quantitative determination of mithramycin in human plasma by a novel, sensitive ultra-HPLC–MS/MS method for clinical pharmacokinetic application

Roth

Peer

Widemann

et al. 2014

Journal of Chromatography B

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“…Mcl-1 has been reported to be a critical survival-promoting molecule in hematopoietic cells, and its overexpression is known to be associated with a variety of human hematopoietic and lymphoid cancers (22). The anti-apoptotic splice variant of Mcl-1 was also augmented in human oral cancer (23), and our previous study demonstrated that the overexpression of Mcl-1 may be strongly correlated with oral cancer development (24).…”

Section: Discussionmentioning

confidence: 98%

“…Several studies have reported a high expression level of Mcl-1 in tumor cells of human primary squamous cell carcinoma (SCC) and SCC cell lines (24,26). It has been demonstrated that the blockage of its function may play a potentially critical and novel role by the use of either specific siRNA or inhibitor in the treatment of SCC (26).…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we hypothesized that downregulation of Mcl-1 may prevent malignant transformation of OLP to oral cancer. Previously, in vitro and in vivo studies by our group reported that sorafenib and mithramycin A regulated Mcl-1 protein to inhibit the proliferation of oral cancer (24,29). Thus, we assessed the anti-proliferative effect of sorafenib and mithramycin A on MC-3 and HSC-3 cells in order to demonstrate the function of Mcl-1 in the malignant transformation of OLP to oral cancer.…”

Section: Discussionmentioning

confidence: 99%

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Myeloid cell leukemia-1 is a molecular indicator for malignant transformation of oral lichen planus

Shin

Seo

et al. 2016

Oncology Letters

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Abstract. Oral lichen planus (OLP), characterized by a chronic mucocutaneous inflammatory condition, is a common disease of the oral cavity. Retrospective and prospective epidemiological data suggest that OLP is considered to have malignant potential. However, it is unclear as to which types of molecules may cause malignant transformation of OLP. In the present study, the presence of myeloid cell leukemia-1 (Mcl-1) and B-cell lymphoma-2 (Bcl-2) was studied by western blot analysis in 11 OLP and three normal oral mucosa (NOM) samples and in two human oral cancer cell lines. The functional role of Mcl-1 in oral cancer cells was analyzed using a trypan blue exclusion assay and soft agar assay. Mcl-1 was strongly expressed in the OLP and the two oral cancer cell lines compared with NOM, whereas Bcl-2 was not. Sorafenib and mithramycin A decreased cell viability in MC-3 and HSC-3 oral cancer cells and at same concentration they reduced the expression level of Mcl-1 in the two cell lines. The two chemicals affected Mcl-1 protein and significantly inhibited neoplastic cell transformation in the two cell lines. We suggest that the malignant potential of OLP may be associated with the expression of Mcl-1, and that downregulation of Mcl-1 may prevent malignant transformation of OLP to oral cancer.

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“…Other cytokines and pathways closely associated with OSCC include cyclooxygenase-2 (Chan et al, 1999), myeloid cell leukemia-1 (Shin et al, 2013), serine/threonine kinase signaling pathway (Gao et al, 2013) and PD-1/PD-L1 (the inhibitory receptor Programmed Death-1/Programmed cell death ligand 1) pathway (Lyford-Pike et al, 2013).…”

Section: Bioinformatics Analysis Reveals Significant Genes and Pathwamentioning

confidence: 99%

Bioinformatics Analysis Reveals Significant Genes and Pathways to Targetfor Oral Squamous Cell Carcinoma

Jiang

Yu²,

Ding³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Mithramycin A Inhibits Myeloid Cell Leukemia-1 to Induce Apoptosis in Oral Squamous Cell Carcinomas and Tumor Xenograft through Activation of Bax and Oligomerization

Abstract: In several human malignancies, overexpression of myeloid cell leukemia-1 (Mcl-1) confers resistance to induction of apoptosis; however, Mcl-1-mediated inhibition of apoptosis in oral squamous cell carcinoma (OSCC) is not fully understood and has been investigated in this study.

Cited by 29 publications

References 38 publications

Quantitative determination of mithramycin in human plasma by a novel, sensitive ultra-HPLC–MS/MS method for clinical pharmacokinetic application

Quantitative determination of mithramycin in human plasma by a novel, sensitive ultra-HPLC–MS/MS method for clinical pharmacokinetic application

Myeloid cell leukemia-1 is a molecular indicator for malignant transformation of oral lichen planus

Bioinformatics Analysis Reveals Significant Genes and Pathways to Targetfor Oral Squamous Cell Carcinoma

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