Tanshinone IIa Induces Autophagy and Apoptosis via PI3K/Akt/mTOR Axis in Acute Promyelocytic Leukemia NB4 Cells

Abstract

Tanshinone IIa (TanIIa), an ingredient of Radix Salviae Miltiorrhizae, has an anticancer effect on various solid tumors with high efficiency and low toxicity. Nonetheless, the underlying role of TanIIa in acute promyelocytic leukemia (APL) remains unclear. Here, we revealed that TanIIa drastically inhibited NB4 cell viability with an IC50 value of 31.25 μmol/L. Using flow cytometry apoptosis assay, we identified that TanIIa dose-dependently exacerbated NB4 cell apoptosis. Mechanistically, TanIIa upregulated apoptotic factor levels, namely, cleaved-caspase 9, cleaved-caspase 3, and cleaved-PARP-1. Moreover, we noticed that TanIIa dose-dependently suppressed the PI3K/Akt/mTOR axis. This axis not only functions as an essential antiapoptotic modulator but also serves as a suppressant regulator of autophagy. Correspondingly, we detected the levels of autophagic marker, namely, LC3B, which were increased after the TanIIa treatment. Furthermore, the autophagy inhibitor Baf-A1 could effectively reverse the TanIIa-induced apoptosis, manifesting that TanIIa eliminated NB4 cells in an autophagy-dependent manner. In conclusion, tanshinone IIa exerts anti-APL effects through triggering autophagy and apoptosis in NB4 cells.

The mechanisms of tanshinone in the treatment of tumors

“…Similarly, Ding et al (2017) found that tan IIA blocked the PI3K/Akt/mTOR pathway and lowered p-PI3K and p-Akt levels in U251 glioma cells, inducing autophagy and inhibiting cell viability. In acute promyelocytic leukemia, tan IIA blocked the PI3K/Akt/mTOR axis and promoted autophagy of NB4 cells, decreasing PI3K, Akt, and mTOR protein levels while raising p-ULK-1 and LC3B levels ( Pan et al, 2021 ). Similar to these results, tan IIA inhibited PI3K/Akt/mTOR to trigger acute myeloid leukemia U937 cell death and autophagy in vitro and in vivo ( Zhang et al, 2019c ).…”

Untitled

“…Most terpenoids are isolated from medicinal plants that belong to the following plant groups: Oleaceae, Rutaceae, Labiatae, Acanthaceae, Compositae, Taxaceae, Pinaceae, Lauraceae, Araliaceae, Celastraceae, etc. Terpenoids are classified according to the number of isoprene (2-methylbuta-1, 3-diene) units into monoterpenoids (C 10 ), Menthol Peppermint oil (Mentha piperita) [17] Myrcene bay laurel oil (Laurus nobilis) and Verbena oil (Lippia citriodora) [18] Perillyl alcohol [19] Eucalyptol (1.8-cineole) Eucalyptus leaf oil (Eucalyptus globules), rosemary (Rosmarinus officinalis) [20] Sesquiterpenoids Artemisinin and its derivatives Sweet wormwood (Artemisia annua) [21] Costunolide Aucklandia lappa [22,23] Diterpenoids Acanthoic acid Acanthopanax koreanum Nakai, Croton oblongifolius Roxb [24,25] Oridonin Rabdosia rubescens [26] Tanshinone IIA Salvia miltiorrhiza Bge [27] Taxol (Paclitaxel) Taxus brevifolia [28] Triptolide Tripterygium wilfordii [29,30] Kaurenoic acid Annona senegalensis (Annonaceae) [31] Triterpenoids Celastrol Tripterygium wilfordii [29] Withaferin A Withania somnifera [32] Ursolic acid Rosmarinus officinalis (rosemary), Calluna vulgaris and Eugenia jambolana, Salvia officinalis, and Eriobotrya japonica [33] Tetraterpenoids Lycopene Tomatoes (Lycopersicon esculentum), pink guavas, apricots, water melon, and pink grapefruits [34,35] Lutein Spinach, kale, carrot, corn, and egg yolk [36,37] β-carotene Carrot [38] sesquiterpenoids (C 15 ), diterpenoids (C 20 ), triterpenoids (C 30 ), tetraterpenoids (C 40 ), and polyterpenoids (C > 40) [Table 1]. They possess vast medicinal importance that includes: antitumor, antibacterial, antimalarial, anti-inflammatory, antiviral, anticancer, immunomodulatory, anti-aging, antioxidant, anti-depressants, antifungal, and antidiabetic.…”

“…It also facilitates the phagocytosis of apoptotic tumor cells through the regulation of macrophage functioning that involves tumor necrosis factor (TNF)-α and interleukin-1β. [27,59,60] It is effective against breast, colon, pancreatic, lung, gastric, prostate, and skin cancers. [61] Tanshinone IIA Its antitumor/cancer activity is attributed to its tumor growth inhibition, apoptosis induction, signaling pathway, and cell cycle regulation.…”

Salvia miltiorrhiza in cancer: Potential role in regulating MicroRNAs and epigenetic enzymes

“…The PI3K/Akt and MAPK/MEK/ERK1/2 signaling pathways have a positive regulatory effect on mTOR, and blocking the above pathways causes autophagy, eventually leading to tumor cell death ( Xu et al, 2020a ). It has been reported that tan I and tan IIA induce autophagy by inhibiting the PI3K/Akt/mTOR pathway, further inhibiting the proliferation of tumor cells (including ovarian cancer cells, glioma cells, acute promyelocytic leukemia NB4 cells, acute mononuclear leukemia cells, oral squamous cell carcinoma (OSCC) cells, and melanoma cells) ( Ding et al, 2017 ; Li et al, 2017 ; Qiu et al, 2018 ; Zhang et al, 2019c ; Zhou et al, 2020b ; Pan et al, 2021 ). In addition, tan IIA also drives autophagy through inhibiting the MEK/ERK/mTOR signaling pathway, thereby suppressing the proliferation of colon cancer cells ( Qian et al, 2020 ).…”