| In vitro: |
| Carcinogenesis. 2019 Aug 27. pii: bgz140. | | Synergistic anti-breast cancer effect of pulsatilla saponin D and camptothecin through interrupting autophagic-lysosomal function and promoting p62-mediated ubiquitinated protein aggregation.[Pubmed: 31504230 ] | Autophagy is an evolutionarily conserved mechanism to protect the cells from unfavorable environmental conditions. Inhibition of autophagy has been contemplated as a novel strategy to enhance anticancer efficacy of existing chemotherapeutic agents. We previously reported that pulsatillasaponin D (PSD) was a potent autophagy inhibitor. However, its anticancer potential as adjuvant and underlying mechanisms are still unknown.
METHODS AND RESULTS:
In this study, we identified that PSD induced the formation of autophagosome in MCF-7 and MDA-MB-231 breast cancer cells. However, PSD alone and particularly co-treatment with camptothecin remarkably increased p62 protein levels, indicating that PSD strongly inhibited the autophagic cargo degradation. The mechanistic study indicated that PSD profoundly abolished the co-localization of EGFP-LC3 and lysosomal-specific probe LysoTracker Red, suggesting that the autophagosome-lysosome fusion was blocked by PSD, which is similar to the action of chloroquine. In addition, PSD significantly increased lysosomal pH and inhibited the activation of lysosomal cathepsins in both breast cancer cell lines. Furthermore, the accrued p62 resulted in accumulation of ubiquitinated proteins owing to the interaction with p62 and delivery to the malfunctioned autophagosome by PSD. Finally, we demonstrated that PSD synergistically enhanced the anticancer activity of camptothecin (CPT) in cultured breast cancer cells and in mouse xenograft tumor models.
CONCLUSIONS:
Our results indicated that PSD inhibited autophagic flux via blocking autophagosome-lysosome fusion and lysosomal acidification, which may confer a synergistic anti-breast cancer activity of PSD and CPT. | | Oncol Rep . 2013 Aug;30(2):801-8. | | SB365, Pulsatilla saponin D suppresses proliferation and induces apoptosis of pancreatic cancer cells[Pubmed: 23733203] | | Pulsatilla koreana has been used as a traditional medicine for the treatment of various diseases. The purpose of this study was to determine whether SB365, Pulsatilla saponin D isolated from the root of Pulsatilla koreana inhibits the progression of pancreatic cancer. We found that SB365 strongly suppressed the growth and proliferation of 5 human pancreatic cancer cell lines (MIAPaCa-2, BXPC-3, PANC-1, AsPC-1 and HPAC). The apoptotic effect of SB365 was demonstrated by increased levels of cleaved caspase-3 and decreased Bcl-2 expression via mitochondrial membrane potential, as well as elevated numbers of terminal deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL)-positive apoptotic cells. SB365 was also found to exert an anti-angiogenic effect by decreasing the expression of HIF-1α and VEGF, major factors of angiogenesis, which was confirmed by the suppression of tumor sphere formation of pancreatic cancer cells. An in vivo mouse xenograft study showed that SB365 significantly inhibited tumor growth through the induction of apoptosis and inhibition of angiogenesis with strong anticancer activity. Therefore, SB365 is a good candidate as a natural product for use in the treatment of pancreatic cancer. | | Food Chem . 2013 Jan 1;136(1):26-33. | | SB365, Pulsatilla saponin D suppresses the proliferation of human colon cancer cells and induces apoptosis by modulating the AKT/mTOR signalling pathway[Pubmed: 23017388] | | Pulsatilla koreana has been used as a traditional medicine for the treatment of several diseases. The purpose of this study was to determine if SB365, Pulsatilla saponin D isolated from the root of P. koreana inhibits the progression of colon cancer. We found that SB365 strongly suppressed the growth and proliferation of colon cancer cells and induced their apoptosis. Also, SB365 showed anti-angiogenic activity by decreasing the expression of HIF-1α and VEGF. These results were confirmed by an in vivo study showing that SB365 significantly inhibited tumor growth by the induction of apoptosis and inhibition of angiogenesis with stronger anticancer activity than 5-FU. When further examined for its anticancer mechanism, SB365 effectively suppressed the AKT/mTOR pathway both in vitro and in vivo. Taken together, our study demonstrated that SB365 inhibits the AKT/mTOR pathway, leading to the suppression of tumor growth and angiogenesis together with induction of apoptosis. Therefore, SB365 is a good candidate as a natural product for use in the treatment of colon cancer. |
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