Polyphyllin I and VII potentiate the chemosensitivity of A549/DDP cells to cisplatin by enhancing apoptosis, reversing EMT and suppressing the CIP2A/AKT/mTOR signaling axis

Abstract

Poor response and resistance to cisplatin (DDP)-based chemotherapy frequently leads to treatment failure in advanced non-small cell lung cancer (NSCLC). The underlying molecular mechanism is extremely complex and currently remains unclear. The overexpression of cancerous inhibitor of protein phosphatase 2A (CIP2A) indicates poor prognosis and promotes the epithelial-to-mesenchymal transition (EMT) and metastasis. The EMT has been reported to promote drug resistance in numerous previous studies. CIP2A and its downstream protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway also plays a role in mediating DDP resistance. Polyphyllin I (PPI) and polyphyllin VII (PPVII) are natural components extracted from Paris polyphylla that display anti-cancer properties. In the present study, the chemosensitizing effects of PPI and PPVII were investigated in the DDP-resistant NSCLC cell line A549/DDP, as well as the underlying molecular mechanisms. The results demonstrated that PPI and PPVII could significantly inhibit cell proliferation and enhance the sensitivities of A549/DDP cells to DDP. When assessing the underlying molecular mechanism, it was revealed that PPI and PPVII enhanced DDP-induced apoptosis in A549/DDP cells via p53 upregulation and the caspase-dependent pathway. Furthermore, PPI and PPVII reversed the EMT and suppressed CIP2A and its downstream AKT/mTOR signaling cascade in A549/DDP cells. Overall, the results from the present study demonstrated that PPI and PPVII may function as chemosensitizers by enhancing apoptosis via the p53 pathway, reversing EMT and suppressing the CIP2A/AKT/mTOR signaling axis, and the combination with DDP may be a promising strategy for the development of new therapeutic agents.

Cordycepin Reverses Cisplatin Resistance in Non-small Cell Lung Cancer by Activating AMPK and Inhibiting AKT Signaling Pathway

“…It should be noted that many of the studies that define the apoptotic function of p53 is dependent on several DDP-induced upstream signaling pathways that activate the tumor-suppressor protein by upregulating this phosphorylation ( Fritsche et al, 1993 ; Feng et al, 2019 ). AMPK activation is also revealed to cause cell cycle arrest associated with stabilization of p53 and the cyclin-dependent kinase inhibitor p27 ( Wang et al, 2016 ).…”

“…Previous studies indicate that dysregulation of AKT is a prominent feature of various tumors including NSCLC ( Lee et al, 2002 ; Liao et al, 2019 ). In addition, AKT amplification and the mTOR signaling pathway also play an important role in mediating DDP resistance in lung cancer ( Feng et al, 2019 ).…”

Cordycepin Reverses Cisplatin Resistance in Non-Small Cell Lung Cancer by Activating AMPK and Inhibiting the AKT Signaling Pathway

“…It should be noted that many of the studies to de ne the apoptotic function of p53 is dependent on several DDP-induced upstream signaling pathways that activate the tumor-suppressor protein by upregulating tis phosphorylation (20,39). AMPK activation is also revealed to cause cell cycle arrest associated with stabilization of p53 and the cyclin-dependent kinase inhibitor p27 (14).…”

“…Previous studies indicate that dysregulation of AKT is a prominent feature of various tumors including NSCLC (18,19). In addition, AKT ampli cation and the mTOR signal pathway also play an important role in mediating DDP resistance in lung cancer (20).…”

Natural Products Targeting the Mitochondria in Cancers

“…They can be used—not only as a complementary and alternative therapy—but also to enhance the efficacy of resistant cell lines. Combination with cisplatin and chrysin promotes the apoptosis of HepG2 cells by upregulating p53 [ 160 ], polyphyllin I enhances apoptosis and suppresses the CIP2A/AKT/mTOR signaling pathway in A549/DDP cells [ 161 ]. Combining ginsenoside compound K with cisplatin produced a better effect on the apoptosis and epithelial mesenchymal transition through the PI3K/Akt pathway in MCF-7 cells [ 162 ].…”