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Published on: May 14, 2016
Y9, a Gboxin analog, displays anti-tumor effect in non-small cell lung cancer by inducing lysosomal dysfunction and
Jie Yin1, Longjie Ding1, Si Yao1
1Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Abstract:
Non-small cell lung cancer (NSCLC) ranks among the most prevalent malignancies globally. Gboxin, a novel inhibitor of mitochondrial complex V that exerts unique anti-tumor effects via oxidative phosphorylation inhibition, but shows no efficacy against NSCLC in vivo. Through chemical structure optimization, we designed and synthesized Gboxin analog Y9, which demonstrates significantly enhanced potency over its predecessor. Specifically, Y9 inhibited NSCLC significantly more strongly than Gboxin and possessed the ability to inhibit cell cycle progression and induce oxidative stress similar to Gboxin. Further investigation revealed that unlike Gboxin, Y9 selectively acidifies lysosomes and induces lysosomal dysfunction. This leads to hyperactive autophagy with impaired substrate clearance, and ultimately resulting in apoptosis. Animal studies confirmed the efficacy of Y9 in suppressing tumor growth in a xenograft mouse model. Collectively, Y9 is a distinctive Gboxin analog that outperforms its prototype by inducing lysosomal dysfunction and apoptosis, and has the potential to be developed as a novel anti-NSCLC lead compound.
Insights
A new compound, Y9, effectively targets non-small cell lung cancer (NSCLC) by inducing lysosomal dysfunction and apoptosis, offering a promising new lead compound for NSCLC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Non-small cell lung cancer (NSCLC) is a leading global malignancy.
- Gboxin, a mitochondrial complex V inhibitor, shows anti-tumor effects but lacks in vivo efficacy for NSCLC.
Purpose of the Study:
- To design and synthesize a novel Gboxin analog, Y9, with enhanced potency against NSCLC.
- To elucidate the mechanism of action of Y9 in NSCLC cells.
Main Methods:
- Chemical structure optimization and synthesis of Gboxin analog Y9.
- In vitro assays assessing cell cycle progression, oxidative stress, lysosomal function, and autophagy.
- In vivo studies using a xenograft mouse model.
Main Results:
- Y9 demonstrated significantly enhanced potency against NSCLC compared to Gboxin.
- Y9 induced cell cycle arrest, oxidative stress, lysosomal dysfunction, and hyperactive autophagy with impaired substrate clearance.
- Y9 effectively suppressed tumor growth in a xenograft mouse model.
Conclusions:
- Y9 is a potent Gboxin analog that overcomes the limitations of its predecessor.
- Y9's mechanism involves inducing lysosomal dysfunction and apoptosis, leading to effective tumor suppression.
- Y9 shows potential as a novel lead compound for NSCLC therapy.
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