Sarsaparilla (Smilax Glabra Rhizome) Extract Inhibits Cancer Cell Growth by S Phase Arrest, Apoptosis, and Autophagy via Redox-Dependent ERK1/2 Pathway.

Cancer is still the major cause of death across the world. Regular approaches cannot effectively solve the emerging problems, including drug/radiation resistance, side effects, and therapeutic ineffectiveness. Natural dietary supplements have shown effectiveness in the prevention and treatment of cancer. Sarsaparilla (Smilax Glabra Rhizome) has growth-inhibitory effects on several cancer cell lines in vitro and in vivo, with little toxicity on normal cells. However, the mechanism underlying its function remains elusive. In the present study, we examined the anticancer activity of the supernatant of the water-soluble extract (SW) from sarsaparilla. Liquid chromatography/mass spectrometry-ion trap-time-of-flight (LC/MS-IT-TOF) analysis identified flavonoids, alkaloids, and phenylpropanoids as the major bioactive components of SW. SW was shown to markedly inhibit the growth of a broad spectrum of cancer cell lines in the in vitro and in vivo assays. S phase arrest, autophagy, or/and apoptosis were partly responsible for SW-induced growth inhibition. Results of microarray analysis and validation by quantitative RT-PCR indicated the involvement of oxidative stress and the MAPK1 pathway in SW-treated cells. We further found that SW destroyed intracellular-reduced glutathione/oxidized glutathione (GSH/GSSG) balance, and supplement with N-acetylcysteine (NAC) or glutathione (GSH) significantly antagonized SW-induced S phase arrest, apoptosis, and autophagy. In addition, SW-induced GSH/GSSG imbalance activated the ERK1/2 pathway, which contributed to SW-induced S phase arrest, apoptosis, autophagy, and resultant growth-inhibitory effect. Together, our results provide a molecular basis for sarsaparilla as an anticancer agent.