TY - JOUR
T1 - Anticancer activity of a broccoli derivative, sulforaphane, in barrett adenocarcinoma
T2 - Potential use in chemoprevention and as adjuvant in chemotherapy
AU - Qazi, Aamer
AU - Pal, Jagannath
AU - Maitah, Ma'in
AU - Fulciniti, Mariateresa
AU - Pelluru, Dheeraj
AU - Nanjappa, Puru
AU - Lee, Saem
AU - Batchu, Ramesh B.
AU - Prasad, Madhu
AU - Bryant, Christopher S.
AU - Rajput, Samiyah
AU - Gryaznov, Sergei
AU - Beer, David G.
AU - Weaver, Donald W.
AU - Munshi, Nikhil C.
AU - Goyal, Raj K.
AU - Shammas, Masood A.
N1 - Funding Information:
Address all correspondence to: Masood A. Shammas, PhD, Harvard (Dana Farber) Cancer Institute, Boston, MA, Harvard Medical School at VAMC, 1400 VFW Pkwy, Bldg 3, Room 2A111, West Roxbury, MA 02132. E-mail: masood_shammas@dfci.harvard.edu 1This work was supported by grants from R01CA125711 to MAS, from the Department of Veterans Affairs Merit Review Awards and from the National Institutes of Health grant RO1-124929 to NCM and grants P50-100007 and PO1-78378 to NCM and Dr. K. C. Anderson and by funds from Karmanos Cancer Institute and Department of Surgery, Wayne State University, Detroit, MI. 2AQ, JP, and MM contributed equally to this work. Received 22 September 2010; Revised 6 October 2010; Accepted 9 October 2010 Copyright © 2010 Neoplasia Press, Inc. All rights reserved 1944-7124/10/$25.00 DOI 10.1593/tlo.10235
PY - 2010/12
Y1 - 2010/12
N2 - INTRODUCTION: The incidence of Barrett esophageal adenocarcinoma (BEAC) has been increasing at an alarming rate in western countries. In this study, we have evaluated the therapeutic potential of sulforaphane (SFN), an antioxidant derived from broccoli, in BEAC. METHODS: BEAC cells were treated with SFN, alone or in combination with chemotherapeutic, paclitaxel, or telomerase-inhibiting agents (MST-312, GRN163L), and live cell number determined at various time points. The effect on drug resistance/chemosensitivity was evaluated by rhodamine efflux assay. Apoptosis was detected by annexin V labeling and Western blot analysis of poly(ADP-ribose) polymerase cleavage. Effects on genes implicated in cell cycle and apoptosis were determined by Western blot analyses. To evaluate the efficacy in vivo, BEAC cells were injected subcutaneously in severe combined immunodeficient mice, and after the appearance of palpable tumors, mice were treated with SFN. RESULTS: SFN induced both time- and dose-dependent decline in cell survival, cell cycle arrest, and apoptosis. The treatment with SFN also suppressed the expression of multidrug resistance protein, reduced drug efflux, and increased anticancer activity of other antiproliferative agents including paclitaxel. A significant reduction in tumor volume was also observed by SFN in a subcutaneous tumor model of BEAC. Anticancer activity could be attributed to the induction of caspase 8 and p21 and down-regulation of hsp90, a molecular chaperon required for activity of several proliferation-associated proteins. CONCLUSIONS: These data indicate that a natural product with antioxidant properties from broccoli has great potential to be used in chemoprevention and treatment of BEAC.
AB - INTRODUCTION: The incidence of Barrett esophageal adenocarcinoma (BEAC) has been increasing at an alarming rate in western countries. In this study, we have evaluated the therapeutic potential of sulforaphane (SFN), an antioxidant derived from broccoli, in BEAC. METHODS: BEAC cells were treated with SFN, alone or in combination with chemotherapeutic, paclitaxel, or telomerase-inhibiting agents (MST-312, GRN163L), and live cell number determined at various time points. The effect on drug resistance/chemosensitivity was evaluated by rhodamine efflux assay. Apoptosis was detected by annexin V labeling and Western blot analysis of poly(ADP-ribose) polymerase cleavage. Effects on genes implicated in cell cycle and apoptosis were determined by Western blot analyses. To evaluate the efficacy in vivo, BEAC cells were injected subcutaneously in severe combined immunodeficient mice, and after the appearance of palpable tumors, mice were treated with SFN. RESULTS: SFN induced both time- and dose-dependent decline in cell survival, cell cycle arrest, and apoptosis. The treatment with SFN also suppressed the expression of multidrug resistance protein, reduced drug efflux, and increased anticancer activity of other antiproliferative agents including paclitaxel. A significant reduction in tumor volume was also observed by SFN in a subcutaneous tumor model of BEAC. Anticancer activity could be attributed to the induction of caspase 8 and p21 and down-regulation of hsp90, a molecular chaperon required for activity of several proliferation-associated proteins. CONCLUSIONS: These data indicate that a natural product with antioxidant properties from broccoli has great potential to be used in chemoprevention and treatment of BEAC.
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U2 - 10.1593/tlo.10235
DO - 10.1593/tlo.10235
M3 - Article
AN - SCOPUS:78650323904
SN - 1944-7124
VL - 3
SP - 389
EP - 399
JO - Translational Oncology
JF - Translational Oncology
IS - 6
ER -