Sodium Tanshinone IIA Sulfonate Attenuates Tumor Oxidative Stress and Promotes Apoptosis in an Intermittent Hypoxia Mouse Model

Abstract

Objective: Intermittent hypoxia, a significant feature of obstructive sleep apnea, has pro-tumorigenic effects. Here, we investigated the effect of sodium tanshinone IIA sulfonate on oxidative stress and apoptosis in a mouse model of Lewis lung carcinoma with intermittent hypoxia. Methods: Mice were randomly assigned to normoxia (control), normoxia plus sodium tanshinone IIA sulfonate (control + sodium tanshinone IIA sulfonate), intermittent hypoxia, and intermittent hypoxia + sodium tanshinone IIA sulfonate groups. Intermittent hypoxia administration lasted 5 weeks in the intermittent hypoxia groups. Lewis lung carcinoma cells were injected into the right flank of each mouse after 1 week of intermittent hypoxia exposure. Sodium tanshinone IIA sulfonate was injected intraperitoneally in the control + sodium tanshinone IIA sulfonate and intermittent hypoxia + sodium tanshinone IIA sulfonate groups. Tumor oxidative stress was evaluated by detection of malondialdehyde and superoxide dismutase. The apoptosis of tumor cells was evaluated by the terminal deoxynucleotidyl transferase dUTP nick-end labeling assay as well as by Western blot analysis of B-cell lymphoma 2-associated X protein and cleaved caspase-3 expression. Additionally, the expression of hypoxia-induced factor-1α, nuclear factor erythroid 2-related factor 2, and nuclear factor kappa B was also evaluated by Western blot. Results: Compared with the control group, the intermittent hypoxia treatment significantly increased Lewis lung carcinoma tumor growth and oxidative stress (serum malondialdehyde) but decreased serum levels of SOD and pro-apoptotic markers (terminal deoxynucleotidyl transferase dUTP nick-end labeling staining, B-cell lymphoma 2-associated X protein, and cleaved caspase-3). These changes were significantly attenuated by intraperitoneal injection of sodium tanshinone IIA sulfonate. Lower nuclear factor erythroid 2-related factor 2 and higher nuclear factor kappa B levels in the intermittent hypoxia group were clearly reversed by sodium tanshinone IIA sulfonate treatment. In addition, sodium tanshinone IIA sulfonate administration decreased the high expression of hypoxia-induced factor-1α induced by intermittent hypoxia. Conclusion: Intermittent hypoxia treatment resulted in high oxidative stress and low apoptosis in Lewis lung carcinoma–implanted mice, which could be attenuated by sodium tanshinone IIA sulfonate administration possibly through a mechanism mediated by the nuclear factor erythroid 2-related factor 2/nuclear factor kappa B signaling pathway.

Sodium tanshinone IIA sulfonate inhibits tumor growth via miR-138 upregulation in intermittent hypoxia-induced xenograft mice

“…According to the IH exposure, TSA administration, miR-138 agomir, and antagomir injection, the animals were randomized as CTL, IH, IH + TSA, IH + TSA + miR-138 mimic, and IH + miR-138 inhibitor groups. Under IH conditions, mice were placed in a chamber, with oxygen content altering from 21% to nadir 6%–8% within 120 s for an 8-h period every daytime for 5 weeks consecutively, as mentioned previously [ 6 ]. During the experiment, animals were kept in standard cages with the 12-h/12-h high-dark cycle, with free access to food and water.…”

“…At 1-week post-IH exposure, mice were subcutaneously injected with LLC cells (1 × 10 6 /100 μL of PBS) in the right flank. After the tumor grew to an appropriate volume (around 5–7 days post-LLC administration), TSA (10 mg/kg) was administered to the animals in IH + TSA and IH + TSA + miR-138 inhibitor groups daily through intraperitoneal injection [ 6 ]. Mice in the IH + TSA + miR-138 inhibitor group received miR-138 antagomir intratumoral injection (25 nmol diluted in 100 μL of PBS per mouse), whereas those in the IH + miR-138 mimic group received miR-138 agomir injection (25 nmol per mouse).…”

“…Sodium tanshinone IIA sulfonate (TSA), extracted from the Chinese herbal medicine Salvia miltiorrhiza , is a natural compound with anti-oxidation and anti-inflammatory properties [ 14 ]. We have previously demonstrated that TSA can reverse the IH-induced tumor high oxidative stress and low apoptosis levels [ 6 ]. However, the exact mechanism remains unclear.…”

Targeting Oxidative Stress and Endothelial Dysfunction Using Tanshinone IIA for the Treatment of Tissue Inflammation and Fibrosis

“…For example, TanIIA reduced oxidative stress in the serum of tumor-bearing mice by combining intermittent hypoxia. TanIIA promotes apoptosis of tumor cells, which may be related to the activation of Nrf2 [ 65 ]. Similar protective effects were also observed in mice with experimental pancreatitis [ 66 ].…”

Tanshinone analog inhibits castration-resistant prostate cancer cell growth by inhibiting glycolysis in an AR-dependent manner

“…On this basis, we have derived a series of chemical compounds. Among them, TB3 was obtained by introducing the aromatic ring fragment at the benzyl position of the furan ring ( 16 ). It was found that the novel tanshinone analog, TB3, significantly inhibits the proliferation and cell cycle of PCa cells, and has lower cytotoxicity to human normal liver than other tanshinone analogs.…”