Salidroside enhances the anti-cancerous effect of imatinib on human acute monocytic leukemia via the induction of autophagy-related apoptosis through AMPK activation

Abstract

As the typical tyrosine kinase inhibitor, imatinib has been the first-line antineoplastic agent for both chronic myeloid leukemia and acute lymphoblastic leukemia. However, a large number of patients are still resistant to the benefits of imatinib, and they have a dissatisfactory prognosis. Salidroside, a compound that is extracted from natural plants, has been reported to have an excellent anticancer effect and few side effects. In the present study, we have developed a new combination therapy strategy of salidroside and imatinib for combating the growth of acute lymphoblastic leukemia. As demonstrated by the anti-proliferation assay, salidroside exhibited excellent cytotoxicity against myeloid leukemia cells. Moreover, cells treated by the combination therapy of salidroside and imatinib displayed a clear lower growth rate than cells only treated by imatinib, indicating that salidroside has a positive effect on enhancing the cytotoxicity of imatinib against leukemia cells. Subsequently, the underlying mechanisms were investigated. The results revealed that autophagy marker proteins in leukemia cells, including LC3, p62, and Beclin1, displayed a significant expression change after treating them with salidroside plus imatinib, with the levels of LC3 and Beclin1 dramatically increasing while the expression of p62 was significantly decreased. Moreover, an obvious downregulation of p-PI3K, p-AKT and p-mTOR expression levels in leukemia cells after treatment with salidroside plus imatinib suggested that the PI3K/mTOR pathway plays an important role in the process of cell apoptosis induced by salidroside or imatinib. Further studies showed that pre-incubating the cells with an autophagy inhibitor dramatically inhibited the ability of imatinib to induce autophagy, but did not inhibit the ability of salidroside. The underlying causes were subsequently explored and the results showed that silencing AMPKa1, the most important regulator of autophagy, dramatically attenuates the ability of salidroside to induce cell apoptosis. These results together indicated that salidroside enhances the cytotoxicity of imatinib on acute monocytic leukemia via the induction of autophagy-related apoptosis through AMPK activation. The unique advantages of combination therapy were further confirmed by in vivo experiments, with the tumor-bearing cells treated with salidroside plus imatinib achieving the best anti-tumor effect. Fig. 1 Cell viabilities of THP-1 and U937 cells after receiving therapy with salidroside, imatinib, or the combination therapy strategy. (A) Salidroside exists in Rhodiola rosea, and the molecular structure is shown. THP-1 and U937 cells were treated with different concentrations of imatinib (B) and salidroside (C) for 48 h, and the cell viability was detected by a CCK-8 assay. For further determination of the ratio of salidroside and imatinib in the combination therapy strategy, both THP-1 and U937 cells were treated by various combination therapy strategies: 2 mM salidroside + 10 mM imatinib (D), 2 mM salidroside + 20 m...

Traditional Tibetan Medicine in Cancer Therapy by Targeting Apoptosis Pathways

“…(2011) . It is worth noting that salidroside could induce the autophagy-related apoptosis on human acute monocytic leukemia cells (THP-1 and U937) through AMPK activation via downregulating p62, p-PI3K, p-AKT, and p-mTOR expressions and upregulating Beclin1, LC3II and AMPK expressions ( Ge et al., 2019 ).…”

“…Ethanol extract of Swertia mussotii , ethanol extract of Meconopsis horridula (Fan et al, 2015b), ethanol extract of Meconopsis integrifolia (Fan et al, 2015a), cordycepin (Chaicharoenaudomrung et al, 2018), salidroside (Zhao G. et al, 2015), gallic acid (Wang R. et al, 2016), berberine (Xie et al, 2015), TC-2 (Sharma et al, 2018), and ellagic acid (Ceci et al, 2018) PI3K/Akt Ethanol extract of Rhodiola kirilowii (Wang and Lin, 2015), cordycepin (Yoon et al, 2018), gallic acid (VerMa et al, 2013, berberine (Chen, 2016), salidroside (Ge et al, 2019), waltonitone (Zhang et al, 2009), and ellagic acid (Ceci et al, 2018)…”

“…Salidroside (Kang et al, 2018), 2-acetyl-benzylamine (Balachandran et al, 2017), crocin (Hoshyar and Mollaei, 2017), berberine (Li J. et al, 2018), and ellagic acid (Ceci et al, 2018) NF-kB Ethanol extract of Gentianopsis paludosa (Lu et al, 2016), polysaccharide of Cordyceps sinensis (Jayakumar et al, 2014), cordycepin (Yoon et al, 2018), salidroside (Li and Chen, 2017), gallic acid (Verma et al, 2013), berberine (Li J. et al, 2018), palmatine (Hambright et al, 2015), and ellagic acid (Ceci et al, 2018) MAPK Tannin fraction of Phyllanthus emblica (Zhao H.J. et al, 2015), polysaccharide of Cordyceps sinensis (Jayakumar et al, 2014), cordycepin (Yoon et al, 2018), salidroside (Zhao G. et al, 2015), berberine (Chen et al, 2019), waltonitone (Zhang F.G. et al, 2010), and ellagic acid (Ceci et al, 2018) AMPK Salidroside (Ge et al, 2019) and berberine (Pan et al, 2017) proliferation, and differentiation of various cells (Zhao H. J. et al, 2015). More and more studies have shown that the MAPK pathway plays important roles in the process of apoptosis transduction and is significantly related to the occurrence and development of breast, ovarian, esophageal, colon, stomach, and liver cancers (Yoon et al, 2018).…”

A global bibliometric and visualized analysis of the links between the autophagy and acute myeloid leukemia

“…Meanwhile, Ge CY et al found that salidroside enhances the anti-tumor effect of imatinib in AML by activating autophagy and increasing its cytotoxicity against acute monocytic leukemia. ( Ge et al, 2019 ). These studies indicate that targeting autophagy and combination therapy have achieved some results in vitro experiments on AML drug resistance, but there is still a lack of safety evaluation and clinical validation.…”