Abstract
Fungal secondary metabolites serve as a rich resource for exploring lead compounds with medicinal importance. Diorcinol N (DN), a fungal secondary metabolite isolated from an endophytic fungus, Arthrinium arundinis, exhibits robust anticancer activity. However, the anticancer mechanism of DN remains unclear. In this study, we examined the growth-inhibitory effect of DN on different human cancer cell lines. We found that DN decreased the viability of A3 T-cell leukemia cells in a time- and concentration-dependent manner. Transcriptome analysis indicated that DN modulated the transcriptome of A3 cells. In total, 9,340 differentially expressed genes were found, among which 4,378 downregulated genes and 4,962 upregulated genes were mainly involved in autophagy, cell cycle, and DNA replication. Furthermore, we demonstrated that DN induced autophagy, cell cycle arrest in the G1/S phase, and downregulated the expression of autophagy- and cell cycle-related genes in A3 cells. By labeling A3 cells with acridine orange/ethidium bromide, Hoechst 33,258, and monodansylcadaverine and via transmission electron microscopy, we found that DN increased plasma membrane permeability, structural disorganization, vacuolation, and autophagosome formation. Our study provides evidence for the mechanism of anticancer activity of DN in T-cell leukemia (A3) cells and demonstrates the promise of DN as a lead or even candidate molecule for the treatment of acute lymphoblastic leukemia.
Highlights
Acute lymphoblastic leukemia (ALL) is a hematological malignancy associated with uncontrolled proliferation and transformation of lymphoid progenitor cells within the bone marrow (Soulier and Cortes, 2015)
The results indicate a significant increase in the expression of genes involved in the promotion of autophagy (AMPK, beclin-1, autophagy-related gene 1 (ATG1), vacuolar protein sorting 34 (VPS34), and autophagy-related gene 7 (ATG7)) and a reduction in the expression of genes involved in the inhibition of autophagy (PI3K and mammalian target of rapamycin (mTOR)) (Figure 7A)
We provide evidence that Diorcinol N (DN) inhibited growth and induced autophagy in leukemia cells by modulating multiple cell signaling molecules
Summary
Acute lymphoblastic leukemia (ALL) is a hematological malignancy associated with uncontrolled proliferation and transformation of lymphoid progenitor cells within the bone marrow (Soulier and Cortes, 2015). Over the past few decades, the revolution in tumor cell biology and chemotherapeutic strategies coupled with high-throughput sequencing has led to significant improvement in outcomes for pediatric patients (Hunger and Mullighan, 2015). The survival rate of leukemia patients can reach 90% in children under 14 years of age, while it can decrease to 40% in adults between 25 and years of age and to almost 15% in adults aged over (Curran and Stock, 2015; Hunger and Mullighan, 2015; Kansagra et al, 2018). There is an urgent need to develop novel therapies that overcome resistance to the currently administered anticancer drugs for ALL cells
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