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|Title:||Inhibition of TFF3 enhances sensitivity—and overcomes acquired resistance—to doxorubicin in estrogen receptor-positive mammary carcinoma||Authors:||Poh, H.M.
Basappa, Department of Studies in Organic Chemistry, University of Mysore, Mysore, 570005, India.
Trefoil factor 3 (TFF3)
|Issue Date:||2019||Publisher:||MDPI AG||Citation:||Poh, H.M., Chiou, Y.S., Chong, Q.Y., Chen, R.-M., Rangappa, K.S., Ma, L., Zhu, T., Kumar, A.P., Pandey, V., Basappa, Department of Studies in Organic Chemistry, University of Mysore, Mysore, 570005, India., Lee, S.-C., Lobie, P.E. (2019). Inhibition of TFF3 enhances sensitivity—and overcomes acquired resistance—to doxorubicin in estrogen receptor-positive mammary carcinoma. Cancers 11 (10) : 1528. ScholarBank@NUS Repository. https://doi.org/10.3390/cancers11101528||Rights:||Attribution 4.0 International||Abstract:||Dose-dependent toxicity and acquired resistance are two major challenges limiting the efficacious treatment of mammary carcinoma (MC) with doxorubicin. Herein, we investigated the function of Trefoil Factor 3 (TFF3) in the sensitivity and acquired resistance of estrogen receptor positive (ER+) MC cells to doxorubicin. Doxorubicin treatment of ER+MC cells increased TFF3 expression. The depletion of TFF3 by siRNA or inhibition with a small molecule TFF3 inhibitor (AMPC) synergistically enhanced the efficacy of doxorubicin in ER+MC through the suppression of doxorubicin-induced AKT activation and enhancement of doxorubicin-induced apoptosis. Elevated expression of TFF3 and increased activation of AKT were also observed using a model of acquired doxorubicin resistance in ER+MC cells. AMPC partially re-sensitized the doxorubicin resistant cells to doxorubicin-induced apoptosis. Indeed, doxorubicin resistant ER + MC cells exhibited increased sensitivity to AMPC as a single agent compared to doxorubicin sensitive cells. In vivo, AMPC attenuated growth of doxorubicin sensitive ER+MC xenografts whereas it produced regression of xenografts generated by doxorubicin resistant ER+MC cells. Hence, TFF3 inhibition may improve the efficacy and reduce required doses of doxorubicin in ER+MC. Moreover, inhibition of TFF3 may also be an effective therapeutic strategy to eradicate doxorubicin resistant ER+MC. © 2019 by the authors. Licensee MDPI, Basel, Switzerland.||Source Title:||Cancers||URI:||https://scholarbank.nus.edu.sg/handle/10635/209544||ISSN:||2072-6694||DOI:||10.3390/cancers11101528||Rights:||Attribution 4.0 International|
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