Paris saponin VII induces cell cycle arrest and apoptosis by regulating Akt/MAPK pathway and inhibition of P‐glycoprotein in K562/ADR cells

Abstract

Paris saponinVII (PSVII) is a steroidal saponin isolated from the roots and rhizomes of Trillium tschonoskii Maxim. We found that PSVII could inhibit the growth of adriamycin-resistant human leukemia cells (K562/ADR) in a dose-dependent manner. Furthermore, the molecular mechanism underlying the cytotoxicity and downregulation of P-glycoprotein (P-gp) expression by PSVII was clarified. PSVII significantly suppressed cell proliferation by cell cycle arrest in the G0/G1 phase, which was associated with an obvious decrease in cyclin B1/D1 and CDK2/4/6 protein expression. Moreover, PSVII could attenuate mitochondrial membrane potential, increase the expression of apoptosis-related proteins, such as Bax and cytochrome c, and decrease the protein expression levels of Bcl-2, caspase-9, caspase-3, PARP-1, and p-Akt. We also found that JNK, ERK1/2, and p38 were regulated by PSVII in K562/ADR cells. And further studies indicated that the decrease in the reactive oxygen species level inhibited intrinsic P-gp expression. Therefore, PSVII-induced apoptosis in K562/ADR cells was associated with Akt/MAPK and the inhibition of P-gp. In addition, PSVII induced a robust autophagy in K562/ADR cells as demonstrated by the degradation of LC3-I. These results provide a biochemical basis for possible clinical applications of PSVII in the treatment of leukemia.

Paris saponin VII enhanced the sensitivity of HepG2/ADR cells to ADR via modulation of PI3K/AKT/MAPK signaling pathway

“…On the contrary, reversing the high expressions of BCRP and MRP may partially restore the sensitivity of some tumor cells to chemotherapeutics, including HCC . In our research, we found that PS VII could significantly reduce the expression of P‐gp, MRP and BCRP in a concentration‐dependent manner in HepG2/ADR cells treat with ADR, which was similar to those findings by the previous researchers, representing the increased sensitivity of PS VII to the HepG2/ADR cells to ADR. A previous study reported that P‐gp can pump out antitumor drugs from cells through an energy‐dependent mechanism, leading to the reduction of cellular drug concentration and cytotoxicity and further inducing the generation of MDR .…”

“…In this article, the HepG2/ADR cells were treated with different concentrations of PS VII (including 0.88, 1.32, and 1.98 μM) and ADR (5 nM), which could concentration dependently reduce the proliferative ability, leading to a significantly lower IC50 value than cells treated with ADR (5 nM) alone, suggesting that PS VII reversed the drug resistance of HepG2/ADR cells toward ADR. Consistent with our result, PS VII could limit the growth of ADR‐resistant human leukemia cells (K562/ADR) in a dose‐dependent manner from the work by Yan and the colleagues . Also, Li et al observed the influenced cell viability of MCF‐7/ADR cells after treatment with PS VII, and the increased sensitivity to the cytotoxic effects of ADR .…”

“…For example, PS VII enhanced the sensitivity to gefitinib in acquired resistant NSCLC cells in the work of Wang et al and inhibited chemoresistance in breast cancer in the study of He et al Besides, there was evidence pointed out that PS VII could play its regulatory role via modulation of the PI3K/AKT/MAPK signaling pathway, including reversing the ADR resistance of tumor cells. As demonstrated by Yan et al, PS VII could induce the cell cycle arrest and apoptosis to inhibit the growth of K562/ADR cells through regulating PI3K/AKT/MAPK signaling pathway . Nevertheless, whether PS VII can mediate the PI3K/AKT/MAPK signaling pathway to reverse the multidrug resistance of HepG2/ADR cells is unclear.…”

Pulchinenosides from Pulsatilla Chinensis Increase P‐Glycoprotein Activity and Induce P‐Glycoprotein Expression

“…In terms of the influence of pulchinenosides on P-glycoprotein function, 48 h exposure to pulchinenosides appeared to consistently increase P-glycoprotein expression in the LS180 cells, although the mechanism has yet to be identified. In contrast to most steroidal saponins [37] that might downregulate P-gp expression, pulchinenosides exposure leads to the upregulation of P-gp/ABCB1 state. Potential mechanisms involved within the induction of P-gp functional activity, and expression could involve the Pregnane x Receptor (PXR) [38], protein kinase C [39], and the Figure 8: RT-polymerase chain reaction analysis of multidrug resistance gene 1 mRNA in LS180 cells exposed to pulchinenosides for 48 hours (n � 3, mean ± SD).…”

New Steroidal Saponins Isolated from the Rhizomes of Paris mairei

“…It has been used as a traditional Chinese medicine for traumatic injuries, heat-clearing and detoxifying, and relief of swelling and long-term pain [2]. Under the development of phytochemistry, steroidal saponins have been proved to be the main chemicals in the genus Paris and present a wide range of pharmacological activities such as anti-tumor [3][4][5], anti-inflammatory [6], anti-fungal [7], hemostasis [8], and immunomodulatory [9]. Moreover, Rhizoma Paridis, documented as rhizomes of Paris polyphylla var.…”