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

• Published in: Biomedicine & pharmacotherapy Vol. 163; p. 114865
• Main Authors: Li, Shuangting, Wang, Diancan, Zheng, Xuan, Li, Yi, Ding, Chong, Wang, Meng, Ge, Xuejun, Jiang, Jiuhui, Qiao, Yan, Wang, Yixiang
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.07.2023; Elsevier
• Subjects: Akt/HK2/cyclin D1 axis; Cell Line, Tumor; Cell Proliferation; Cyclin D1 - metabolism; Glucose - pharmacology; Glucose deprivation; Humans; Melanoma; Melanoma - drug therapy; Melanoma - pathology; Niclosamide; Niclosamide - pharmacology; Niclosamide - therapeutic use; Proto-Oncogene Proteins c-akt - metabolism; Quinacrine; Quinacrine - pharmacology; Signal Transduction; Niclosamide; Akt/HK2/cyclin D1 axis; Quinacrine; Glucose deprivation; Melanoma
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2023.114865

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. [Display omitted] •Glucose plays an essential role in melanoma cell proliferation.•Niclosamide and quinacrine combination inhibits melanoma proliferation.•Niclosamide and quinacrine combination inhibits melanoma proliferation through inactivating Akt/HK2/Cyclin D1 axis mediated by glucose deprivation.