Tan IIA inhibits H1299 cell viability through the MDM4‑IAP3 signaling pathway

Abstract

Tanshinone IIA (Tan IIA), as a bioactive compound extracted from the dried roots of Salvia miltiorrhiza (also known as Danshen), is known to inhibit cancer cell proliferation and induce apoptosis. However, the mechanisms underlying the function of Tan IIA in cancer cell apoptosis remain to be elucidated The aim of the present study was to identify the molecular mechanisms underlying the anti-cancer effects of Tan IIA in p53-deficient H1299 cells. Tan IIA was demonstrated to suppress murine double minute 4 (MDM4) expression in a time- and dose-dependent manner through the inhibition of MDM4 mRNA synthesis. Tan IIA-induced downregulation of MDM4 resulted in an increase of P73α and a decrease of inhibitor of apoptosis 3 (IAP3). However, P73α was not activated as two P73α target genes, BCL2 binding component 3 and phorbol-12-myristate-13-acetate-induced protein 1, were not significantly induced. Tan IIA-induced inhibition of IAP3 expression may be involved in Tan IIA-induced apoptosis and inhibition of H1299 cell viability. Notably, a combination of Tan IIA and doxorubicin (DOX) exposure resulted in further MDM4 overexpression in H1299 cells, indicating that Tan IIA sensitized p53-deficient and MDM4-overexpressing H1299 cells to DOX-induced apoptosis.

The Anticancer Properties of Tanshinones and the Pharmacological Effects of Their Active Ingredients

“…Furthermore, Tan IIA could inhibit osteosarcoma MG-63 cell proliferation and achieve its best inhibitory effect with 8.8 mg/L of Tan IIA (Zhang et al, 2012b;Ma et al, 2016a,b). Tan IIA treatment also induced cell apoptosis and arrested cell cycle in human oral cancer KB cells line by mitochondrial pathway via activation of caspase-3, caspase-9, and PARP (Tseng et al, 2014), by MDM4-IAP3 signaling pathway in lung cancer H1299 cells (Zu et al, 2018), and by inducing the formation of cleaved caspase-8 and cleavage of RIP1, RIP3, and MLKL in human hepatocellular carcinoma HepG2 cells (Lin C. Y. et al, 2016).…”

Targeting MDMX for Cancer Therapy: Rationale, Strategies, and Challenges

“…Several small-molecule inhibitors of MDMX expression have been developed to inhibit both the p53-dependent and the p53-independent functions of MDMX, such as XI-006 (NSC207895) ( 102 ), XI-011 ( 104 ), luteolin ( 105 ), tanshinone IIA ( 106 ), 25-OCH3-PPD ( 107 ), ASO ( 108 ), and GSK3203591 ( 109 ). However, inhibiting the expression of a molecular target often causes unexpected adverse effects ( 123 , 124 ).…”

“…The importance of the miR-34a-5p-MDMX axis in the anticancer activity of luteolin has also been validated using the transient transfection experiments of a miR-34a-5p inhibitor (105). Zu et al have recently characterized tanshinone IIA as a new MDMX inhibitor (106). Tanshinone IIA has been found to inhibit MDMX expression by repressing MDMX mRNA synthesis, which leads to the downregulation of IAP3 (Inhibitor of apoptosis 3) (106).…”

“…Zu et al have recently characterized tanshinone IIA as a new MDMX inhibitor ( 106 ). Tanshinone IIA has been found to inhibit MDMX expression by repressing MDMX mRNA synthesis, which leads to the downregulation of IAP3 (Inhibitor of apoptosis 3) ( 106 ). Further studies have shown that tanshinone IIA not only induces the apoptosis of H1299 cells but also enhances the doxorubicin-induced apoptosis ( 106 ).…”

Tanshinone IIA enhances the inhibitory effect of imatinib on proliferation and motility of acute leukemia cell line TIB‑152 in�vivo and in�vitro by inhibiting the PI3K/AKT/mTOR signaling pathway

“…Tanshinone IIA (Tan IIA) is an important active ingredient in Salvia miltiorrhiza and there have been reports on its antitumor effects. Studies confirmed that Tan IIA has antitumor activity in vitro and in vivo, and can induce differentiation, promote apoptosis and inhibit proliferation in various tumor cells (9,10), including leukemic cells (11). Tan IIA exerts a significant growth inhibitory effect on various leukemia cells, such as SUP-B15 (human Ph acute T lymphocytic leukemia cell line), K562 (chronic myeloid leukemia cell line), CEM (human leukemia cell line) and NB4 (acute promyelocytic leukemia cell beads) (12).…”