Mithramycin Represses Basal and Cigarette Smoke–Induced Expression of<i>ABCG2</i>and Inhibits Stem Cell Signaling in Lung and Esophageal Cancer Cells

Zhang, Mary; Mathur, Aarti; Zhang, Yuwei; Xi, Sichuan; Atay, Scott M.; Hong, Julie A.; Datrice, Nicole; Upham, Trevor; Kemp, Clinton D.; Ripley, R. Taylor; Wiegand, Gordon; Avital, Itzhak; Fetsch, Patricia; Mani, Haresh; Zlott, Daniel; Robey, Robert W.; Bates, Susan E.; Li, Xinmin; Rao, Mahadev; Schrump, David S.

doi:10.1158/0008-5472.can-11-3983

Cited by 92 publications

(86 citation statements)

References 48 publications

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“…MYC and KRAS activate a variety of pathways facilitating initiation and progression of lung cancer (24,48), and overexpression of these oncogenes correlates with treatment resistance and poor survival in lung cancer patients (49,50). Collectively, these observations strongly suggest that epigenetic repression of miR-487b enhances stemness phenotype of lung cancers and are consistent with our recent studies demonstrating that cigarette smoke upregulates ABCG2, increases pluripotent side population, and activates a variety of stem cell signaling pathways in lung cancer cells (51). Additional studies using gene expression profiling and flow cytometry techniques are in progress to more comprehensively examine the effects of miR-487b on global gene expression and stem cell phenotype of lung cancer cells and to more precisely define the constituents of cigarette smoke that induce stemness during pulmonary carcinogenesis.…”

Section: Discussionsupporting

confidence: 88%

Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesis

Xu²,

Shan³

et al. 2013

J. Clin. Invest.

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126

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MicroRNAs are critical mediators of stem cell pluripotency, differentiation, and malignancy. Limited information exists regarding microRNA alterations that facilitate initiation and progression of human lung cancers. In this study, array techniques were used to evaluate microRNA expression in normal human respiratory epithelia and lung cancer cells cultured in the presence or absence of cigarette smoke condensate (CSC). Under relevant exposure conditions, CSC significantly repressed miR-487b. Subsequent experiments demonstrated that miR-487b directly targeted SUZ12, BMI1, WNT5A, MYC, and KRAS. Repression of miR-487b correlated with overexpression of these targets in primary lung cancers and coincided with DNA methylation, de novo nucleosome occupancy, and decreased H2AZ and TCF1 levels within the miR-487b genomic locus. Deoxyazacytidine derepressed miR-487b and attenuated CSC-mediated silencing of miR-487b. Constitutive expression of miR-487b abrogated Wnt signaling, inhibited in vitro proliferation and invasion of lung cancer cells mediated by CSC or overexpression of miR-487b targets, and decreased growth and metastatic potential of lung cancer cells in vivo. Collectively, these findings indicate that miR-487b is a tumor suppressor microRNA silenced by epigenetic mechanisms during tobacco-induced pulmonary carcinogenesis and suggest that DNA demethylating agents may be useful for activating miR-487b for lung cancer therapy.

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Section: Discussionsupporting

confidence: 88%

Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesis

Xu²,

Shan³

et al. 2013

J. Clin. Invest.

Self Cite

126

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“…The standard dose of mitoxantrone in humans (10-14 mg/m 2 ) produces peak plasma concentrations in the range of 1.0 mmol/L (30-32), but high-dose regimens using up to 80 mg/m 2 have been tested extensively and have been deemed safe (33). In summary, these results demonstrate that mithramycin A and mitoxantrone exert their antineoplastic activities in GIST cells at concentrations that are relevant for the clinic and can be achieved in the sera of patients with cancer (32,34).…”

Section: A Compound Screen Identifies Inhibitors Of Transcription Andmentioning

confidence: 99%

Unbiased Compound Screening Identifies Unexpected Drug Sensitivities and Novel Treatment Options for Gastrointestinal Stromal Tumors

et al. 2014

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Most gastrointestinal stromal tumors (GIST) are caused by oncogenic KIT or platelet-derived growth factor receptor activation, and the small molecule kinase inhibitor imatinib mesylate is an effective first-line therapy for metastatic or unresectable GIST. However, complete remissions are rare and most patients ultimately develop resistance, mostly because of secondary mutations in the driver oncogenic kinase. Hence, there is a need for novel treatment options to delay failure of primary treatment and restore tumor control in patients who progress under therapy with targeted agents. Historic data suggest that GISTs do not respond to classical chemotherapy, but systematic unbiased screening has not been performed. In screening a compound library enriched for U.S. Food and Drug Administration (FDA)-approved chemotherapeutic agents (NCI Approved Oncology Drugs Set II), we discovered that GIST cells display high sensitivity to transcriptional inhibitors and topoisomerase II inhibitors. Mechanistically, these compounds exploited the cells' dependency on continuous KIT expression and/or intrinsic DNA damage response defects, explaining their activity in GIST. Mithramycin A, an indirect inhibitor of the SP1 transcription factor, and mitoxantrone, a topoisomerase II inhibitor, exerted significant antitumor effects in mouse xenograft models of human GIST. Moreover, these compounds were active in patient-derived imatinib-resistant primary GIST cells, achieving efficacy at clinically relevant concentrations. Taken together, our findings reveal that GIST cells have an unexpectedly high and specific sensitivity to certain types of FDAapproved chemotherapeutic agents, with immediate implications for encouraging their clinical exploration. Cancer Res; 74(4); 1200-13. Ó2014 AACR.

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“…7 MIT was found to reduce drug resistance through downregulation of the xenobiotic pump ABCG2 and the multidrug resistant gene MDR1. 8,9 It was also shown that MIT inhibited DNA methyltransferase (DNMT), histone deacetylase (HDAC), and antiapoptotic protein XIAP. [10][11][12] Preclinical studies demonstrated that MIT can inhibit the generation and progression of several cancers, including carcinomas of the lung, breast, pancreas, stomach, and prostate, as well as sarcoma and glioblastoma.…”

Section: Introductionmentioning

confidence: 99%

“…[10][11][12] Preclinical studies demonstrated that MIT can inhibit the generation and progression of several cancers, including carcinomas of the lung, breast, pancreas, stomach, and prostate, as well as sarcoma and glioblastoma. 8,[13][14][15][16] Meanwhile, its prominent in vitro and in vivo activities linked to specific transcription regulation have triggered the clinical trials of MIT in lung cancer, esophagus cancer, and Ewing sarcoma, sponsored by the National Cancer Institute (NCT01610570, NCT01624090, and NCT02859415, www.ClinicalTrials.gov).…”

Section: Introductionmentioning

confidence: 99%

Mithramycin-loaded mPEG-PLGA nanoparticles exert potent antitumor efficacy against pancreatic carcinoma

Liu

et al. 2017

IJN

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Previous studies have shown that mithramycin A (MIT) is a promising candidate for the treatment of pancreatic carcinoma through inhibiting transcription factor Sp1. However, systemic toxicities may limit its clinical application. Here, we report a rationally designed formulation of MIT-loaded nanoparticles (MIT-NPs) with a small size and sustained release for improved passive targeting and enhanced therapeutic efficacy. Nearly spherical MIT-NPs with a mean particle size of 25.0±4.6 nm were prepared by encapsulating MIT into methoxy poly(ethylene glycol)-block-poly( d , l -lactic- co -glycolic acid) (mPEG-PLGA) nanoparticles (NPs) with drug loading of 2.11%±0.51%. The in vitro release of the MIT-NPs lasted for >48 h with a sustained-release pattern. The cytotoxicity of MIT-NPs to human pancreatic cancer BxPC-3 and MIA Paca-2 cells was comparable to that of free MIT. Determined by flow cytometry and confocal microscopy, the NPs internalized into the cells quickly and efficiently, reaching the peak level at 1–2 h. In vivo fluorescence imaging showed that the prepared NPs were gradually accumulated in BxPC-3 and MIA Paca-2 xenografts and retained for 168 h. The fluorescence intensity in both BxPC-3 and MIA Paca-2 tumors was much stronger than that of various tested organs. Therapeutic efficacy was evaluated with the poorly permeable BxPC-3 pancreatic carcinoma xenograft model. At a well-tolerated dose of 2 mg/kg, MIT-NPs suppressed BxPC-3 tumor growth by 96%. Compared at an equivalent dose, MIT-NPs exerted significantly higher therapeutic effect than free MIT (86% versus 51%, P <0.01). Moreover, the treatment of MIT and MIT-NPs reduced the expression level of oncogene c-Myc regulated by Sp1, and notably, both of them decreased the protein level of CD47. In summary, the novel formulation of MIT-NPs shows highly therapeutic efficacy against pancreatic carcinoma xenograft. In addition, MIT-NPs can downregulate CD47 expression, implying that it might play a positive role in cancer immunotherapy.

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Mithramycin Represses Basal and Cigarette Smoke–Induced Expression ofABCG2and Inhibits Stem Cell Signaling in Lung and Esophageal Cancer Cells

Cited by 92 publications

References 48 publications

Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesis

Cigarette smoke mediates epigenetic repression of miR-487b during pulmonary carcinogenesis

Unbiased Compound Screening Identifies Unexpected Drug Sensitivities and Novel Treatment Options for Gastrointestinal Stromal Tumors

Mithramycin-loaded mPEG-PLGA nanoparticles exert potent antitumor efficacy against pancreatic carcinoma

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