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Synergistic glycolysis disturbance for cancer therapy by a MOF-based nanospoiler
Xuemei Zeng1, Yihang Ruan1, Lun Wang2
1Key Laboratory of Innate Immune Biology of Fujian Province, Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, Fuzhou 350117, China.
Abstract:
Increased glycolysis for promoting adenosine triphosphate (ATP) generation is one of the hallmarks of cancer. Although reducing glucose intake or depriving cellular glucose can delay the growth of tumors to some extent, their therapeutic efficacy is a highly needed improvement for clinical translation. Herein, we found that mannose synergistic with glucose oxidase (GOx) can induce cell death by ATP inhibition, autophagy activation, and apoptosis protein upgradation. By using biodegradable zeolitic imidazolate frameworks (ZIF-8) as a nanocarrier (denoted as ZIF-8/M&G), the mannose and GOx can accumulate at the tumor site while having no obvious long-term toxicity. At the tumor site, GOx inhibits glycolysis by converting glucose and oxygen to H 2O 2 and gluconic acid, realizing oxidation therapy and expediting the degradation of the pH-responsive ZIF-8 nanoparticles, respectively. Simultaneously, mannose disturbs sugar metabolism and reduces oxygen consumption, which in turn promotes the GOx oxidation process. The concerted glycolysis inhibition through interactions between mannose and GOx endows ZIF-8/M&G nanospolier with excellent therapeutic efficacy both in vitro and in vivo. Synergistic glycolysis disturbance by the designed nanospoiler in this work proposes a versatile approach for metabolism disturbance to tumor treatment.
Insights
Mannose and glucose oxidase (GOx) synergistically inhibit cancer cell glycolysis, inducing cell death. This combination, delivered via ZIF-8 nanoparticles, offers a promising strategy for cancer metabolism therapy.
Area of Science:
- Biochemistry
- Nanotechnology
- Oncology
Background:
- Cancer cells exhibit increased glycolysis for adenosine triphosphate (ATP) generation, a key hallmark.
- Current strategies to inhibit glycolysis have limited therapeutic efficacy for clinical translation.
Purpose of the Study:
- To investigate the synergistic effect of mannose and glucose oxidase (GOx) in inducing cancer cell death.
- To develop a nanocarrier system for targeted delivery of mannose and GOx to tumor sites.
Main Methods:
- Utilized biodegradable zeolitic imidazolate frameworks (ZIF-8) as nanocarriers for mannose and GOx (ZIF-8/M&G).
- Investigated the mechanism of cell death induction, including ATP inhibition, autophagy activation, and apoptosis.
- Evaluated therapeutic efficacy both in vitro and in vivo.
Main Results:
- ZIF-8/M&G effectively accumulated at the tumor site with no obvious long-term toxicity.
- GOx inhibited glycolysis by producing hydrogen peroxide and gluconic acid, while mannose disturbed sugar metabolism and reduced oxygen consumption.
- The synergistic action of mannose and GOx led to significant cancer cell death and demonstrated excellent therapeutic efficacy.
Conclusions:
- Combined mannose and GOx, delivered by ZIF-8 nanoparticles, effectively inhibit cancer cell glycolysis and induce cell death.
- This synergistic approach offers a versatile strategy for targeting cancer metabolism.
- The developed nanospolier shows potential for improved cancer treatment outcomes.
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