Cephalotaxine Inhibits the Survival of Leukemia Cells by Activating Mitochondrial Apoptosis Pathway and Inhibiting Autophagy Flow

Abstract

Cephalotaxine (CET) is a natural alkaloid with potent antileukemia effects. However, its underlying molecular mechanism has not been well understood. In this study, we verified that CET significantly inhibited the viability of various leukemia cells, including HL-60, NB4, Jurkat, K562, Raji and MOLT-4. RNA-sequencing and bioinformatics analysis revealed that CET causes mitochondrial function change. Mechanism research indicated that CET activated the mitochondrial apoptosis pathway by reducing the mitochondrial membrane potential, downregulating anti-apoptotic Bcl-2 protein and upregulating pro-apoptotic Bak protein. In addition, the autophagy signaling pathway was highly enriched by RNA-seq analysis. Then, we found that CET blocked the fluorescence colocation of MitoTracker Green and LysoTracker Red and upregulated the level of LC3-II and p62, which indicated that autophagy flow was impaired. Further results demonstrated that CET could impair lysosomal acidification and block autophagy flow. Finally, inhibiting autophagy flow could aggravate apoptosis of HL-60 cells induced by CET. In summary, this study demonstrated that CET exerted antileukemia effects through activation of the mitochondria-dependent pathway and by impairing autophagy flow. Our research provides new insights into the molecular mechanisms of CET in the treatment of leukemia.

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“…Leukemia is a blood cancer that leads to high death rate worldwide [ 1 – 3 ]. To date, chemotherapy is the main treatment of leukemia with promising efficacy [ 4 – 6 ]. However, due to the heterogeneity of leukemia cells, no regimen has been shown to be superior in most cases [ 7 , 8 ].…”

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“…Paclitaxel stabilizes microtubules, increases microtubule polymerization, decreases microtubule depolymerization, prevents mitosis, and blocks cell cycle progression 22 . Cephalotaxin inhibits the growth of cancer cells by activating the mitochondrial apoptosis pathway 23 . Fasudil is a calcium channel blocker and inhibits the Rho-kinase signaling pathway [24][25] .…”