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  2. Glutamine Metabolism Targeting Liposomes for Synergistic Chemosensitization and Starvation Therapy in Ovarian Cancer

Glutamine Metabolism Targeting Liposomes for Synergistic Chemosensitization and Starvation Therapy in Ovarian Cancer

  • Acta Biomater. 2022 Dec 31;S1742-7061(22)00865-0. doi: 10.1016/j.actbio.2022.12.052.
Xuzi Cai 1 Si Shi 2 Gui Chen 3 Min Zhong 2 Yuanyuan Yang 4 Ziyi Mai 3 Yang Tian 2 Jinxiu Tan 2 Lijuan He 2 Chunhui Cui 5 Zhiqiang Yu 6 Xuefeng Wang 7
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510632, China; Department of Obstetrics and Gynecology, Guangzhou Women and Children' s Medical Center, Guangzhou 510623, China.
  • 2 Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510632, China.
  • 3 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 4 Department of Laboratory Medicine, Affiliated Dongguan Hospital, Southern Medical University, Dongguan 523018, China.
  • 5 Department of General Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China. Electronic address: drcuich@163.com.
  • 6 Department of Laboratory Medicine, Affiliated Dongguan Hospital, Southern Medical University, Dongguan 523018, China. Electronic address: yuzq@smu.edu.cn.
  • 7 Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Southern Medical University, Guangzhou 510632, China. Electronic address: douwangxuefeng@163.com.
Abstract

Platinum-based chemotherapy is a first-line therapeutic regimen against ovarian Cancer (OC); however, the therapeutic potential is always reduced by glutamine metabolism. Herein, a valid strategy of inhibiting glutamine metabolism was proposed to cause tumor starvation and chemosensitization. Specifically, reactive oxygen species-responsive liposomes were developed to co-deliver cisplatin (CDDP) and bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) [C@B LPs]. The C@B LPs induced effective tumor cell starvation and significantly sensitized OC cells to CDDP by reducing glutathione generation to prevent CDDP detoxification, suppressing ATP production to avoid CDDP efflux, hindering nucleotide synthesis to aggravate DNA damage induced by CDDP, and blocking mammalian target of rapamycin (mTOR) signaling to promote cell Apoptosis. More importantly, C@B LPs remarkably inhibited tumor growth in vivo and reduced the side effects. Taken together, this study provided a successful strategy of synergistic chemosensitization and starvation therapy escalating the rate of therapeutic success in OCs. STATEMENT OF SIGNIFICANCE: : This work proposed a valid strategy of inhibiting glutamine metabolism to cause tumor starvation and chemosensitization. Specifically, ROS-responsive liposomes were developed to co-deliver cisplatin CDDP and BPTES [C@B LPs]. The C@B LPs induced effective tumor cell starvation and significantly sensitized OC cells to cisplatin by reducing glutathione generation to prevent cisplatin detoxification, suppressing ATP production to avoid cisplatin efflux, hindering nucleotide synthesis to aggravate DNA damage induced by cisplatin, and blocking mTOR signaling to promote cell Apoptosis. More importantly, C@B LPs remarkably inhibited tumor growth in vivo and reduced the side effects. Taken together, this study provided a successful strategy of synergistic chemosensitization and starvation therapy escalating the rate of therapeutic success in OCs.

Keywords

chemotherapy; cisplatin sensitization; glutamine metabolism; ovarian cancer; starvation therapy.

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Products
  • Cat. No.
    Product Name
    Description
    Target
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  • HY-12683
    98.98%, Glutaminase抑制剂