As one of the leading causes of
cancer-associated mortalities worldwide, the overall survival rate of
osteosarcoma has stably remained at 15-30% for several decades. (3R)- 5,6,7-trihydroxy-3-isopropyl-3-methylisochroman-1-one (TIM), isolated from the whole plant of Selaginella moellendorffii Hieron., has been reported to have pharmacological activities. In the present study, the anti-proliferative effects of TIM against
osteosarcoma were evaluated, and the underlying molecular mechanisms were explored. The results demonstrated that TIM inhibited proliferation and induced apoptosis in U2OS cells. Furthermore, the expression of the
pro-apoptotic protein NOXA in the intrinsic apoptosis pathway was upregulated by TIM, while the expression of myeloid cell
leukemia 1, an
anti-apoptotic protein, was downregulated. In addition, TIM increased the
protein expression of the endoplasmic reticulum stress markers
inositol-requiring
enzyme 1,
activating transcription factor 6 and
glucose-regulated
protein 78. These results suggested that TIM induced ER stress response while activating intrinsic apoptosis. Furthermore, treating
osteosarcoma tumor-bearing mice with TIM significantly inhibited the
tumor growth in the xenograft animal model. Overall, the study results suggested that TIM may serve as a potential
antitumor agent against
osteosarcoma.