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8α-Tigloyloxyhirsutinolide 13-O-acetate is a potent and orally active STAT3 inhibitor. 8α-Tigloyloxyhirsutinolide 13-O-acetate induces early oxidative stress and Pyroptosis, and late DNA damage, cell cycle arrest, Apoptosis in the TNBC cells. 8α-Tigloyloxyhirsutinolide 13-O-acetate suppresses tumor cell growth in vitro and tumor growth in vivo.

8α-Tigloyloxyhirsutinolide 13-O-acetate (R001) (0-30 μM, 72 h) 剂量依赖性地抑制人类癌细胞系的活细胞数量。
8α-Tigloyloxyhirsutinolide 13-O-acetate (0-10 μM, 0-24 h) 仅在 TNBC 细胞中诱导早期细胞焦亡和晚期 DNA 损伤、细胞周期停滞和细胞凋亡。
8α-Tigloyloxyhirsutinolide 13-O-acetate (0-20 μM, 0-48 h) 促进三阴性乳腺癌细胞中 ROS 的诱导。

Cell Proliferation Assay

Cell Line: Multiple human cancer lines, normal human breast epithelial cells and normal human brain microvascular endothelial cells (HBMEC)

Concentration: 0, 1, 2.5, 5, 10, 20, 30 μM

Incubation Time: 72 h

Result: Dose-dependently suppressed the viable cell numbers of the human cancer lines, MDA-MB-468, MDA-MB-231, Panc-1, A549, DU145, HCC1937, and MDA-MB-436 cells with IC50 values of 2.3, 4.4, 4.3, 5.2, 5.8, 6.3, and 7.1 µM, respectively, compared to much weaker effects on the normal human breast epithelial cells, MCF-10A or HBMEC, with IC50 of 23.9 or 14.2 µM, respectively.

Western Blot Analysis

Cell Line: NIH3T3/v-Src fibroblasts, MDA-MB-231, MDA-MB-468, or MCF-10A cells

Concentration: 0, 2, 5, 10, 20 μM

Incubation Time: 30 min, 3 h, 24 h

Result: Suppressed STAT3:STAT3 DNA-binding activity, with IC50 of 5 µM. Showed the inhibition of STAT3 Tyr phosphorylation in time- and dose-dependent manner, while phospho-Ser-STAT3 (pS727-STAT3), pY1068EGFR, and pY-Jak2 were largely unaffected. Attenuated the expression of STAT3 downstream target genes, including c-Myc, Mcl-1, Bcl-2, Bcl-xL, and vascular endothelial growth factor (VEGF) in MDA-MB-468 and MDA-MB-231 cells.

Apoptosis Analysis

Cell Line: Triple-negative breast cancer (TNBC), MDA-MB-231 and MDA-MB-468 cells, or normal human breast epithelial cells, MCF-10A

Concentration: 0, 2.5, 5 or 10 µM

Incubation Time: 6 or 24 h

Result: Showed no significant induction of early apoptosis at 6 h, while the evidence of extensive cell death of 56.2% occurred at later time (24 h), with cleavage of poly (ADP-ribose) polymerase (PARP) and caspase 3 at 24-48 h.

8α-Tigloyloxyhirsutinolide 13-O-acetate (5 mg/kg，口服灌胃，每周 5 次，持续 75 天) 抑制小鼠肿瘤生长。

Animal Model: Five-week-old female athymic nude mice (injected subcutaneously in the right flank area with MDA-MB-468 cells in 100 μL PBS)

Dosage: 5 mg/kg

Administration: Oral gavage, every day, 5 times per week for 75 days

Result: Inhibited MDA-MB-468 xenografts growth in mice, with reduced pY705-STAT3, G6PD, TrxR1, and GSH levels.

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