Next Article in Journal
Three-Dimensional Conformal Radiotherapy-Based or Intensity-Modulated Radiotherapy-Based Concurrent Chemoradiotherapy in Patients with Thoracic Esophageal Squamous Cell Carcinoma
Previous Article in Journal
The PAK1-Stat3 Signaling Pathway Activates IL-6 Gene Transcription and Human Breast Cancer Stem Cell Formation
Previous Article in Special Issue
Protein Expression Profiling Identifies Key Proteins and Pathways Involved in Growth Inhibitory Effects Exerted by Guggulsterone in Human Colorectal Cancer Cells
Open AccessArticle

Inhibition of TFF3 Enhances Sensitivity—and Overcomes Acquired Resistance—to Doxorubicin in Estrogen Receptor-Positive Mammary Carcinoma

1
Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore
2
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
3
Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, Shenzhen 518055, China
4
Institution of Excellence, University of Mysore, Mysore 570005, India
5
Shenzhen Bay Laboratory, Shenzhen 518055, China
6
Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei 230027, China
7
National University Cancer Institute, Singapore 119074, Singapore
8
Cancer Program, Medical Science Cluster, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
9
Department of Studies in Organic Chemistry, University of Mysore, Mysore 570005, India
10
Department of Haematology-Oncology, National University Health System, Singapore 119228, Singapore
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(10), 1528; https://doi.org/10.3390/cancers11101528
Received: 13 September 2019 / Revised: 1 October 2019 / Accepted: 5 October 2019 / Published: 10 October 2019
(This article belongs to the Special Issue Apoptosis in Cancer)
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. View Full-Text
Keywords: mammary carcinoma; trefoil factor 3 (TFF3); doxorubicin; dose-dependent toxicity; acquired resistance; apoptosis; PI3K/AKT mammary carcinoma; trefoil factor 3 (TFF3); doxorubicin; dose-dependent toxicity; acquired resistance; apoptosis; PI3K/AKT
Show Figures

Figure 1

MDPI and ACS Style

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; Lee, S.-C.; Lobie, P.E. Inhibition of TFF3 Enhances Sensitivity—and Overcomes Acquired Resistance—to Doxorubicin in Estrogen Receptor-Positive Mammary Carcinoma. Cancers 2019, 11, 1528.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop