2. Academic Validation
  3. ClC-3 silencing mediates lysosomal acidification arrest and autophagy inhibition to sensitize chemo-photothermal therapy

ClC-3 silencing mediates lysosomal acidification arrest and autophagy inhibition to sensitize chemo-photothermal therapy

  • Int J Pharm. 2022 Nov 25:628:122297. doi: 10.1016/j.ijpharm.2022.122297.
Hongyu Zhang 1,  Lanxin Meng 1,  Lei Yin 2,  Taojian Fan 3,  Lan Yu 1,  Shichao Han 4,  Lixia Wang 4,  Weiyuan Liang 2,  Xiaoli Yang 5,  Shiguo Sun 6
Affiliations

Affiliations

  • 1 Key Laboratory of Xinjiang Phytomedicine Resources of Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832002, China.
  • 2 Institute of Microscale Optoelectronics, Collaborative Innovation Centre for Optoelectronic Science & Technology, Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen Key Laboratory of Micro-Nano Photonic Information Technology, Guangdong Laboratory of Artificial Intelligence and Digital Economy (SZ), Shenzhen University, Shenzhen 518060, China; Guangxi Health Commission Key Laboratory of Disease Proteomics Research, Scientifc Research Center, School of Public Health, Guilin Medical University, Guilin 541199, China.
  • 3 Institute of Microscale Optoelectronics, Collaborative Innovation Centre for Optoelectronic Science & Technology, Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, College of Physics and Optoelectronic Engineering, Shenzhen Key Laboratory of Micro-Nano Photonic Information Technology, Guangdong Laboratory of Artificial Intelligence and Digital Economy (SZ), Shenzhen University, Shenzhen 518060, China.
  • 4 Department of Gynaecology and Obstetrics, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116027, China.
  • 5 Guangxi Health Commission Key Laboratory of Disease Proteomics Research, Scientifc Research Center, School of Public Health, Guilin Medical University, Guilin 541199, China.
  • 6 Key Laboratory of Xinjiang Phytomedicine Resources of Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832002, China; College of Chemistry and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang 050018, China. Electronic address: [email protected].
PMID: 36261097 DOI: 10.1016/j.ijpharm.2022.122297
Abstract

Protective Autophagy can be activated by external stimuli such as chemotherapy (CT) and photothermal therapy (PTT), leading to tumour resistance. As a key subcellular for Autophagy, lysosomal dysfunction is crucial for Autophagy suppression. Furthermore, lysosomal drug sequestration enhances basic drug resistance such as doxorubicin (DOX), which is trapped away from its target site, namely, the nucleus. Moreover, most of nanodrug delivery systems are internalised to lysosome for degradation, which further leads to DOX resistance. Lysosome serves as an essential organelle in drug resistance mechanisms, whose acidification arrest provides a potential strategy to inhibit Autophagy and lysosomal drug sequestration simultaneously. The chloride channel-3 (ClC-3) protein is known as an important Cl--H+ transporter to maintain lysosomal pH at low values of various human cells. Herein, a black phosphorus-based theranostic nanoplatform of BP-A-S@D is constructed, and HeLa cells are used as a model to verify the effect of ClC-3 on tumour lysosomal acidification and Autophagy regulation. Consequently, ClC-3 silencing inhibits not only protective Autophagy to sensitise chemo-photothermal therapy, but also DOX resistance by suppressing lysosomal acidification. Therefore, ClC-3 silencing could simultaneously inhibit Autophagy and lysosomal drug sequestration to improve anti-tumour efficiency.

Keywords

Autophagy inhibition; Black phosphorus; Chemo-photothermal therapy; ClC-3; Lysosomal drug sequestration; Lysosome acidification.

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