TY - JOUR
T1 - Pluronic block copolymers enhance the anti-myeloma activity of proteasome inhibitors
AU - Hu, Hangting
AU - Petrosyan, Armen
AU - Osna, Natalia A.
AU - Liu, Tong
AU - Olou, Appolinaire A.
AU - Alakhova, Daria Y.
AU - Singh, Pankaj K.
AU - Kabanov, Alexander V.
AU - Faber, Edward A.
AU - Bronich, Tatiana K.
N1 - Funding Information:
This work was supported by the National Institute of Health Institutional Development Award (IDeA) from the National Institute of General Medical Sciences P20GM103480 (TB), the National Institute on Alcohol Abuse and Alcoholism award K01AA022979-01 (AP), and the National Cancer Institute grant R01CA184088 (AVK, DYA), as well as by the China Scholarship Council PhD Scholarship (HH). We thank Dr. Samuel Cohen, Dr. Larisa Poluektova, Dr. Sarah Holstein, Dr. Gleb Haynatzki and Lora Arnold for their support and helpful discussions on this project. We also gratefully acknowledge the assistance of Dr. Fan Lei (purification of Cy5-L61) and Dr. Shaheen Ahmed (biodistribution study). We would like to thank the Confocal Microscopy, Flow Cytometry and Nanomaterials Core Facilities at UNMC.
Publisher Copyright:
© 2019
PY - 2019/7/28
Y1 - 2019/7/28
N2 - Proteasome inhibitors (PIs) have markedly improved response rates as well as the survival of multiple myeloma (MM) patients over the past decade and have become an important foundation in the treatment of MM patients. Unfortunately, the majority of patients either relapses or becomes refractory to proteasome inhibition. This report describes that both PI sensitive and resistant MM cells display enhanced sensitivity to PI in the presence of synthetic amphiphilic block copolymers, Pluronics (SP1017). SP1017 effectively overcomes both acquired resistance and tumor microenvironment-mediated resistance to PIs. The combination of bortezomib and SP1017 augments accumulation of ubiquitinated proteins, increases markers of proteotoxic and ER stress, and ultimately induces both the intrinsic and extrinsic drug-induced apoptotic pathways in MM cells. Notably, co-treatment of bortezomib and SP1017 intensifies SP1017-induced disorganization of the Golgi complex and significantly reduces secretion of paraproteins. Using a human MM/SCID mice model, the combination of bortezomib and SP1017 exerted enhanced antitumor efficacy as compared to bortezomib alone, delaying disease progression, but without additional toxicity. Collectively, these findings provide proof of concept for the utility of combining PI with SP1017 and present a new approach to enhance the efficacy of current treatment options for MM patients.
AB - Proteasome inhibitors (PIs) have markedly improved response rates as well as the survival of multiple myeloma (MM) patients over the past decade and have become an important foundation in the treatment of MM patients. Unfortunately, the majority of patients either relapses or becomes refractory to proteasome inhibition. This report describes that both PI sensitive and resistant MM cells display enhanced sensitivity to PI in the presence of synthetic amphiphilic block copolymers, Pluronics (SP1017). SP1017 effectively overcomes both acquired resistance and tumor microenvironment-mediated resistance to PIs. The combination of bortezomib and SP1017 augments accumulation of ubiquitinated proteins, increases markers of proteotoxic and ER stress, and ultimately induces both the intrinsic and extrinsic drug-induced apoptotic pathways in MM cells. Notably, co-treatment of bortezomib and SP1017 intensifies SP1017-induced disorganization of the Golgi complex and significantly reduces secretion of paraproteins. Using a human MM/SCID mice model, the combination of bortezomib and SP1017 exerted enhanced antitumor efficacy as compared to bortezomib alone, delaying disease progression, but without additional toxicity. Collectively, these findings provide proof of concept for the utility of combining PI with SP1017 and present a new approach to enhance the efficacy of current treatment options for MM patients.
KW - Drug resistance
KW - Multiple myeloma
KW - Pluronic block copolymers
KW - Proteasome inhibitors
KW - Sensitization
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U2 - 10.1016/j.jconrel.2019.05.026
DO - 10.1016/j.jconrel.2019.05.026
M3 - Article
C2 - 31121280
AN - SCOPUS:85067056998
VL - 306
SP - 149
EP - 164
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
ER -