A Second-Generation 2-Methoxyestradiol Prodrug Is Effective against Barrett's Adenocarcinoma in a Mouse Xenograft Model

Kambhampati, Suman; Rajewski, Roger A.; Tanol, Mehmet; Haque, Inamul; Das, Amlan; Banerjee, Snigdha; Jha, Saheli; Burns, Douglas M.; Borrego-Diaz, Emma; Veldhuizen, Peter J. Van; Banerjee, Sushanta K.

doi:10.1158/1535-7163.mct-12-0777

Cited by 25 publications

(17 citation statements)

References 31 publications

(40 reference statements)

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“…Approximately 60% confluent cells were treated with different doses of ASA dissolved in DMSO (SigmaAldrich) or DMSO alone (control) for 72 h. Cellular viability was measured using crystal violet-based cell viability and cytotoxicity assay (CytoSelect TM Cell Viability and Cytotoxicity Assay kits, Cell Biolabs, San Diego, CA, USA) as described earlier by Kambhampati et al 18 and Trypan blue exclusion assay (Life Technologies, Grand Island, NY, USA).…”

Section: Cell Viability Assaymentioning

confidence: 99%

Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition

Maity

Das

et al. 2015

Laboratory Investigation

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Acetylsalicylic acid (ASA), also known as aspirin, a classic, nonsteroidal, anti-inflammatory drug (NSAID), is widely used to relieve minor aches and pains and to reduce fever. Epidemiological studies and other experimental studies suggest that ASA use reduces the risk of different cancers including breast cancer (BC) and may be used as a chemopreventive agent against BC and other cancers. These studies have raised the tempting possibility that ASA could serve as a preventive medicine for BC. However, lack of in-depth knowledge of the mechanism of action of ASA reshapes the debate of risk and benefit of using ASA in prevention of BC. Our studies, using in vitro and in vivo tumor xenograft models, show a strong beneficial effect of ASA in the prevention of breast carcinogenesis. We find that ASA not only prevents breast tumor cell growth in vitro and tumor growth in nude mice xenograft model through the induction of apoptosis, but also significantly reduces the self-renewal capacity and growth of breast tumor-initiating cells (BTICs)/breast cancer stem cells (BCSCs) and delays the formation of a palpable tumor. Moreover, ASA regulates other pathophysiological events in breast carcinogenesis, such as reprogramming the mesenchymal to epithelial transition (MET) and delaying in vitro migration in BC cells. The tumor growth-inhibitory and reprogramming roles of ASA could be mediated through inhibition of TGF-β/ SMAD4 signaling pathway that is associated with growth, motility, invasion, and metastasis in advanced BCs. Collectively, ASA has a therapeutic or preventive potential by attacking possible target such as TGF-β in breast carcinogenesis.

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Section: Cell Viability Assaymentioning

confidence: 99%

Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition

Maity

Das

et al. 2015

Laboratory Investigation

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“…Prior animal and in vitro studies of esophageal adenocarcinoma have shown that E2 57, 58 and 2-methoxyestradiol 59 exhibit anti-carcinogenic properties, and the normal esophagus is known to express certain 17-beta-hydroxysteroid dehydrogenases—such as HSD17B-1, 4, 5, 7, 8, 10 and 11 ( GDS4350 56 GDS1321 42 GDS3472 48 GDS3838 43 )—which indicates that local conversion between estrone and estradiol is possible. Animal and in vitro model systems have not tested the effects of E1.…”

Section: Discussionmentioning

confidence: 99%

Association Between Circulating Levels of Sex Steroid Hormones and Barrett’s Esophagus in Men: A Case–Control Analysis

Cook

Wood

Cash

et al. 2015

Clinical Gastroenterology and Hepatology

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Background & Aims Esophageal adenocarcinoma is believed to result from the progression of gastroesophageal reflux disease to erosive esophagitis and re-epithelialization of the esophagus with a columnar cell population termed Barrett's esophagus (BE). Men develop BE and esophageal adenocarcinoma more frequently than women, and the ratio is increasing; approximately 7 men are diagnosed with malignancy for every woman, yet little is known about the mechanisms of this difference. We assessed whether sex steroid hormones were associated with BE in a male population. Methods We analyzed data from the Barrett's Esophagus Early Detection Case Control Study, based at the Walter Reed National Military Medical Center. Blood samples were collected from 173 men with BE and 213 men without BE (controls, based on endoscopic analysis); 13 sex steroid hormones were measured by mass spectrometry and sex hormone binding globulin was measured by ELISA. We also calculated free estradiol, free testosterone and free dihydrotestosterone (DHT). We used multivariable logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age, race, smoking status, alcohol consumption, body mass index (BMI; kg/m2), heartburn, regurgitation, and gastroesophageal symptom score (excluding heartburn and regurgitation). Results Levels of free testosterone and free DHT were positively associated with BE risk; patients in the highest quartile for these hormones were most likely to have BE (for free testosterone, OR=5.36; 95% CI, 2.21–13.03; P=0.0002 and for free DHT, OR=4.25, 95% CI, 1.87–9.66; P=.001). Level of estrone sulfate was inversely associated with BE risk (P for trend=.02). No other hormone was associated with BE risk. Relationships were not modified by age or BMI. Conclusions In an analysis of men, levels of free testosterone and free DHT were significantly associated with risk of BE.

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“…However, phase II study on relapsed/ refractory diffuse large B cell lymphoma (DLBCL) demonstrated 44 % objective rate achievement [15]. Based on the presence of CD33 on acute myeloid leukemia (AML) blasts and some leukemic stem cells, gemtuzumab ozogamicin (GO), an anti-CD33 antibody carrying the cytotoxic calicheamicin has been developed to treat AML [231]. Several other markers including CD44 [232], IL-3RA or CD123 [233], the immunoglobulin mucin TIM-3 [234] and folate receptor beta (FRβ) [235], have been extensively explored to specifically target leukemic stem cells in human AML.…”

Section: Novel Strategies For Cancer Targeted Deliverymentioning

confidence: 99%

“…[229]. Other derivatives of colchicine [230], estradiol [231], combretastatin [232, 233] and phenstatin [234] have been synthesized and have shown better efficacy relative to parent drug.…”

Section: Prodrug Approach: Analog / Chemical Conjugation For Cancementioning

confidence: 99%

Novel delivery approaches for cancer therapeutics

Mitra

Agrahari

Mandal

et al. 2015

Journal of Controlled Release

130

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Currently, a majority of cancer treatment strategies are based on the removal of tumor mass mainly by surgery. Chemical and physical treatments such as chemo- and radiotherapies have also made a major contribution in inhibiting rapid growth of malignant cells. Furthermore, these approaches are often combined to enhance therapeutic indices. It is widely known that surgery, chemo- and radiotherapy also inhibit normal cells growth. In addition, these treatment modalities are associated with severe side effects and high toxicity which in turn lead to low quality of life. This review encompasses novel strategies for more effective chemotherapeutic delivery aiming to generate better prognosis. Currently, cancer treatment is a highly dynamic field and significant advances are being made in the development of novel cancer treatment strategies. In contrast to conventional cancer therapeutics, novel approaches such as ligand or receptor based targeting, triggered release, intracellular drug targeting, gene delivery, cancer stem cell therapy, magnetic drug targeting and ultrasound-mediated drug delivery, have added new modalities for cancer treatment. These approaches have led to selective detection of malignant cells leading to their eradication with minimal side effects. Lowering, multi-drug resistance and involving influx transportation in targeted drug delivery to cancer cells can also contribute significantly in the therapeutic interventions in cancer.

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A Second-Generation 2-Methoxyestradiol Prodrug Is Effective against Barrett's Adenocarcinoma in a Mouse Xenograft Model

Cited by 25 publications

References 31 publications

Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition

Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition

Association Between Circulating Levels of Sex Steroid Hormones and Barrett’s Esophagus in Men: A Case–Control Analysis

Novel delivery approaches for cancer therapeutics

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