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

Young Mi Whang, Da Hyeon Yoon, Gwang Yong Hwang, Hoyub Yoon, Serk In Park, Young Wook Choi, In Ho Chang

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number3679
Pages (from-to)1-17
Number of pages17
JournalCancers
Volume12
Issue number12
DOIs
Publication statusPublished - 2020 Dec

Keywords

  • AMP activated protein kinase (AMPK)
  • BCG-CWS drug-delivery system
  • Bladder cancer
  • Endoplasmic reticulum (ER) stress
  • Orthotopic bladder cancer mouse model
  • Reactive oxygen species (ROS)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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