Shikonin suppresses proliferation and induces apoptosis in human leukemia NB4 cells through modulation of MAPKs and c-Myc

Abstract

Acute promyelocytic leukemia (APL) is a special subtype of acute myeloid leukemia that responds to treatment with all-trans retinoic acid and arsenic trioxide. However, severe side effects and drug resistance limit the effectiveness of these treatments. Hence, new drugs for APL are required urgently. Shikonin, an active naphthoquinone derived from the Chinese medical herb Zi Cao exerts antitumor activity in several cancers. In the present study, the effects of shikonin on proliferation and apoptosis in NB4 cells, as well as related mechanisms were assessed. Treatment of NB4 cells with shikonin inhibited proliferation in a concentration- and time-dependent manner. The cell cycle was arrested in the G1 phase. NB4 cells treated with shikonin exhibited more apoptosis and higher levels of cleaved caspase-3 and poly ADP-ribose polymerase than control cells. Western blotting results demonstrated that the expression of p-p38 mitogen-activated protein kinase (p-p38MAPK) and p-c-Jun N-terminal kinase (p-JNK) was increased significantly by shikonin treatment, while the expression of p-ERK and c-Myc was decreased. In summary, these findings indicated that shikonin inhibited cell proliferation and induced apoptosis partly through modulation of the MAPKs and downregulation of c-Myc.

Autophagy and Ubiquitin-Mediated Proteolytic Degradation of PML/Rarα Fusion Protein in Matrine-Induced Differentiation Sensitivity Recovery of ATRA-Resistant APL (NB4-LR1) Cells: in Vitro and in Vivo Studies

“…TUNEL detection showed an average increase of 7.27% and 16.73% in the combination group of NB4 and NB4-LR1, respectively. This phenomenon might be ascribed to the upregulated expression of caspase-3 and Bax and the down-regulation of Bcl-2 in the combination group, along with the suppression of c-Myc [27]. Also, a similar change in autophagy and UPP was found in vivo; the combination of ATRA and MAT improved the activity of UPP and autophagy pathway.…”

Shikonin Inhibits Cancer Through P21 Upregulation and Apoptosis Induction

“…The molecular mechanisms underlying the anti-cancer activity of Shikonin seemed to be complicated and may depend on the cellular context (Wang et al, 2019). So far, the reported cellular targets of Shikonin include the pyruvate kinase isoenzyme M2 (PKM2) (Chen et al, 2011;Lu et al, 2018;Tang et al, 2018b), the MAPK pathway (Mao et al, 2008;Zhao et al, 2015;Shan et al, 2017), HIF1a (Li et al, 2017;Han et al, 2018;Tang et al, 2018b), JNK (Zhai et al, 2017;Lin et al, 2018), PI3K/AKT (Zhang et al, 2015;Zhou et al, 2017;Ni et al, 2018;Tang et al, 2018b), STAT3 (Qiu et al, 2017;Tang et al, 2018a), p16INK4A and p73 (Jang et al, 2015), and PTEN (Nigorikawa et al, 2006;Chen et al, 2018;Zhang et al, 2018). These findings, at one hand, demonstrate that Shikonin can regulate various biological processes (Wang et al, 2019).…”

Shikonin inhibits CEBPD downregulation in IL‑17‑treated HaCaT cells and in an imiquimod‑induced psoriasis model

“…A number of studies have suggested that CEBPD transcriptional activation responds to the activation of either STAT3 or p38/CREB (cAMP responsive element binding protein) ( 33 , 47 ). Shan et al ( 48 ) demonstrated that shikonin could inhibit cell proliferation and induce apoptosis by modulating phosphorylated (p)-p38/mitogen-activated protein kinase (MAPK), p-JNK and c-Myc. In addition, ERK, JNK and p38 play important roles in shikonin-induced apoptosis ( 21 , 48 , 49 ).…”

“…Shan et al ( 48 ) demonstrated that shikonin could inhibit cell proliferation and induce apoptosis by modulating phosphorylated (p)-p38/mitogen-activated protein kinase (MAPK), p-JNK and c-Myc. In addition, ERK, JNK and p38 play important roles in shikonin-induced apoptosis ( 21 , 48 , 49 ). The JAK/STAT3 signaling pathway is involved in psoriasis progression and is also targeted by shikonin to reduce tumor growth and metastasis ( 22 , 50 ).…”