TY - JOUR
T1 - Liposome-encapsulated bacillus Calmette–Guérin cell wall skeleton enhances antitumor efficiency for bladder cancer in vitro and in vivo via induction of AMP-activated protein kinase
AU - Whang, Young Mi
AU - Yoon, Da Hyeon
AU - Hwang, Gwang Yong
AU - Yoon, Hoyub
AU - Park, Serk In
AU - Choi, Young Wook
AU - Chang, In Ho
N1 - Funding Information:
Funding: This research was supported by the National Research Foundation (NRF) of the Republic of Korea (NRF-2019R1I1A1A01061485 to Y.M.W.), the Korea Health Technology R&D Project (HI17C0710 to I.H.C.), and the Ministry of Health and Welfare of the Republic of Korea (National R&D Program for Cancer; no. HA17C0040 to S.I.P.).
Funding Information:
This research was supported by the National Research Foundation (NRF) of the Republic of Korea (NRF-2019R1I1A1A01061485 to Y.M.W.), the Korea Health Technology R&D Project (HI17C0710 to I.H.C.), and the Ministry of Health and Welfare of the Republic of Korea (National R&D Program for Cancer; no. HA17C0040 to S.I.P.).
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/12
Y1 - 2020/12
N2 - The Mycobacterium Bacillus Calmette-Guérin cell wall skeleton (BCG-CWS), the main immune active center of BCG, is a potent candidate non-infectious immunotherapeutic drug and an alternative to live BCG for use against urothelial carcinoma. However, its application in anticancer therapy is limited, as BCG-CWS tends to aggregate in both aqueous and non-aqueous solvents. To improve the internalization of BCG-CWS into bladder cancer cells without aggregation, BCG-CWS was nanoparticulated at a 180 nm size in methylene chloride and subsequently encapsulated with conventional liposomes (CWS-Nano-CL) using an emulsified lipid (LEEL) method. In vitro cell proliferation assays showed that CWS-Nano-CL was more effective at suppressing bladder cancer cell growth compared to nonenveloped BCG-CWS. In an orthotopic implantation model of luciferase-tagged MBT2 bladder cancer cells, encapsulated BCG-CWS nanoparticles could enhance the delivery of BCG-CWS into the bladder and suppress tumor growth. Treatment with CWS-Nano-CL induced the inhibition of the mammalian target of rapamycin (mTOR) pathway and the activation of AMP-activated protein kinase (AMPK) phosphorylation, leading to apoptosis, both in vitro and in vivo. Furthermore, the antitumor activity of CWS-Nano-CL was mediated predominantly by reactive oxygen species (ROS) generation and AMPK activation, which induced endoplasmic reticulum (ER) stress, followed by c-Jun N-terminal kinase (JNK) signaling-mediated apoptosis. Therefore, our data suggest that the intravesical instillation of liposome-encapsulated BCG-CWS nanoparticles can facilitate BCG-CW cellular endocytosis and provide a promising drug-delivery system as a therapeutic strategy for BCG-mediated bladder cancer treatment.
AB - The Mycobacterium Bacillus Calmette-Guérin cell wall skeleton (BCG-CWS), the main immune active center of BCG, is a potent candidate non-infectious immunotherapeutic drug and an alternative to live BCG for use against urothelial carcinoma. However, its application in anticancer therapy is limited, as BCG-CWS tends to aggregate in both aqueous and non-aqueous solvents. To improve the internalization of BCG-CWS into bladder cancer cells without aggregation, BCG-CWS was nanoparticulated at a 180 nm size in methylene chloride and subsequently encapsulated with conventional liposomes (CWS-Nano-CL) using an emulsified lipid (LEEL) method. In vitro cell proliferation assays showed that CWS-Nano-CL was more effective at suppressing bladder cancer cell growth compared to nonenveloped BCG-CWS. In an orthotopic implantation model of luciferase-tagged MBT2 bladder cancer cells, encapsulated BCG-CWS nanoparticles could enhance the delivery of BCG-CWS into the bladder and suppress tumor growth. Treatment with CWS-Nano-CL induced the inhibition of the mammalian target of rapamycin (mTOR) pathway and the activation of AMP-activated protein kinase (AMPK) phosphorylation, leading to apoptosis, both in vitro and in vivo. Furthermore, the antitumor activity of CWS-Nano-CL was mediated predominantly by reactive oxygen species (ROS) generation and AMPK activation, which induced endoplasmic reticulum (ER) stress, followed by c-Jun N-terminal kinase (JNK) signaling-mediated apoptosis. Therefore, our data suggest that the intravesical instillation of liposome-encapsulated BCG-CWS nanoparticles can facilitate BCG-CW cellular endocytosis and provide a promising drug-delivery system as a therapeutic strategy for BCG-mediated bladder cancer treatment.
KW - AMP activated protein kinase (AMPK)
KW - BCG-CWS drug-delivery system
KW - Bladder cancer
KW - Endoplasmic reticulum (ER) stress
KW - Orthotopic bladder cancer mouse model
KW - Reactive oxygen species (ROS)
UR - http://www.scopus.com/inward/record.url?scp=85098508220&partnerID=8YFLogxK
U2 - 10.3390/cancers12123679
DO - 10.3390/cancers12123679
M3 - Article
AN - SCOPUS:85098508220
VL - 12
SP - 1
EP - 17
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 12
M1 - 3679
ER -