4.7 Article

Combination of niclosamide and quinacrine inactivates Akt/HK2/Cyclin D1 axis mediated by glucose deprivation towards the inhibition of melanoma cell proliferation

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BIOMEDICINE & PHARMACOTHERAPY
卷 163, 期 -, 页码 -

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ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2023.114865

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Quinacrine; Niclosamide; Melanoma; Akt; HK2; cyclin D1 axis; Glucose deprivation

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Malignant melanoma, an aggressive and lethal skin cancer, lacks effective treatment methods. This study demonstrated the essential role of glucose in melanoma proliferation and identified a drug combination of niclosamide and quinacrine that could inhibit melanoma growth and glucose intake. The mechanism of action was found to involve the suppression of the Akt pathway and the inhibition of the key enzyme HK2 in glucose metabolism. The decrease of HK2 further inhibited cyclin D1 and melanoma cell proliferation. Overall, this research provides evidence for a potential anti-melanoma strategy based on drug-induced glucose deprivation.
Malignant melanoma is one of the most aggressive and lethal skin cancer. At present, the treatment methods for melanoma have shortcomings. Glucose is the primary energy source of cancer cells. However, it is unclear whether glucose deprivation can be used to treat melanoma. Herein, we first found glucose played an essential role in melanoma proliferation. We then further found a drug combination of niclosamide and quinacrine could inhibit melanoma proliferation and glucose intake. Thirdly, we revealed the mechanism of anti-melanoma effect of the drug combination, which suppressed the Akt pathway. In addition, the first-rate limiting enzyme HK2 of glucose metabolism was inhibited. This work also disclosed that the decrease of HK2 inhibited cyclin D1 by reducing the activity of transcription factor E2F3, which further suppressed the proliferation of melanoma cells. The drug combination treatment also resulted in significant tumor regression in the absence of obvious morphologic changes in primary organ in vivo. In summary, our study demonstrated that the drug combination treatment created glucose deprivation to inactive the Akt/HK2/cyclin D1 axis, thereby inhibited the proliferation of melanoma cells, providing a potential anti-melanoma strategy.

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