TY - JOUR
T1 - A second-generation proteasome inhibitor and doxorubicin modulates IL-6, pSTAT-3 and NF-kB activity in MDA-MB-231 breast cancer cells
AU - Vyas, Dinesh
AU - Lopez-Hisijos, Nicolas
AU - Shah, Pranav
AU - Deshpande, Kaivalya S.
AU - Basson, Marc D.
AU - Vyas, Arpita
AU - Chaturvedi, Lakshmi S.
N1 - Funding Information:
Grant Support: We are grateful to the National Institutes of Health (NIH; BIRCWH) grant K12 to Dinesh Vyas that supported this work.
Publisher Copyright:
Copyright © 2017 American Scientific Publishers All rights reserved.
PY - 2017
Y1 - 2017
N2 - Triple-Negative Breast Cancer (TNBC) has a poor prognosis due to lack of targeted therapy. Doxorubicin (DOX) has failed for multiple reasons, including development of multi-drug resistance, induction of inflammation (IL-6 secretion) and long-term toxicities. DOX is also known to have off target proteasomal activation, justifying the concept of combining it with a proteasomal inhibitor. Our study investigated the therapeutic potential of an irreversible proteasome inhibitor carfilzomib (CARF) alone or in combination with DOX in two TNBC cell lines (MDA-MB-231 and MDA-MB-468). CARF was as effective in inhibiting mitosis in vitro for both cell lines in comparison to DOX alone. CARF performed similar to DOX in inhibiting apoptosis but had better results in reducing proliferation. Further studies in MDA-MB-231 cells demonstrated that CARF also inhibited pro-inflammatory IL-6 secretion and NF κB transcriptional activity while DOX stimulated both IL-6 and NF kappa-B activity. The reduction of IL-6 while using CARF highlights its therapeutic potential and ability to enhance current clinical drug regimens. Furthermore, exogenous administration of IL-6 potentiated NF Kappa B transcriptional activity, pSTAT3 (Tyr705) and JAK inflammatory signaling as well as cell proliferation in CARF- or DOX-treated MDA-MB-231 cells. In vivo, CARF treatment resulted in reduced serum IL-6 compared to treatment with DOX in female SCID-NOD mice with MDA-MB-231 cell tumor. A combinational approach using DOX and CARF presents a clinical potential for better efficacy, reduced proliferation, apoptosis, anti-angiogenesis, and less cardiac dysfunction when compared to current treatments using standalone DOX.
AB - Triple-Negative Breast Cancer (TNBC) has a poor prognosis due to lack of targeted therapy. Doxorubicin (DOX) has failed for multiple reasons, including development of multi-drug resistance, induction of inflammation (IL-6 secretion) and long-term toxicities. DOX is also known to have off target proteasomal activation, justifying the concept of combining it with a proteasomal inhibitor. Our study investigated the therapeutic potential of an irreversible proteasome inhibitor carfilzomib (CARF) alone or in combination with DOX in two TNBC cell lines (MDA-MB-231 and MDA-MB-468). CARF was as effective in inhibiting mitosis in vitro for both cell lines in comparison to DOX alone. CARF performed similar to DOX in inhibiting apoptosis but had better results in reducing proliferation. Further studies in MDA-MB-231 cells demonstrated that CARF also inhibited pro-inflammatory IL-6 secretion and NF κB transcriptional activity while DOX stimulated both IL-6 and NF kappa-B activity. The reduction of IL-6 while using CARF highlights its therapeutic potential and ability to enhance current clinical drug regimens. Furthermore, exogenous administration of IL-6 potentiated NF Kappa B transcriptional activity, pSTAT3 (Tyr705) and JAK inflammatory signaling as well as cell proliferation in CARF- or DOX-treated MDA-MB-231 cells. In vivo, CARF treatment resulted in reduced serum IL-6 compared to treatment with DOX in female SCID-NOD mice with MDA-MB-231 cell tumor. A combinational approach using DOX and CARF presents a clinical potential for better efficacy, reduced proliferation, apoptosis, anti-angiogenesis, and less cardiac dysfunction when compared to current treatments using standalone DOX.
KW - Breast cancer
KW - Carfilzomib
KW - Doxorubicin
KW - IL-6
KW - NF-KappaB
KW - pSTAT3
UR - http://www.scopus.com/inward/record.url?scp=85007545503&partnerID=8YFLogxK
U2 - 10.1166/jnn.2017.12427
DO - 10.1166/jnn.2017.12427
M3 - Article
C2 - 29617099
AN - SCOPUS:85007545503
SN - 1533-4880
VL - 17
SP - 175
EP - 185
JO - Journal of Nanoscience and Nanotechnology
JF - Journal of Nanoscience and Nanotechnology
IS - 1
ER -