The synergistic anticancer effect of formosanin C and polyphyllin VII based on caspase‐mediated cleavage of Beclin1 inhibiting autophagy and promoting apoptosis

Abstract

Objectives Drug combination has a promising and potential development prospect in the treatment of various cancers. The objective of this study is to investigate the synergistic mechanisms of polyphyllin VII ( PVII ) and formosanin C ( FC ) in lung cancer. Materials and methods The combination of FC and PVII influenced on the apoptosis, autophagy, and the relative signalling pathways were analysed in lung cancer cells. Results The combination of FC and PVII demonstrated a concentration‐ dependent growth inhibition in human lung cancer cells. The combination index ( CI ) obtained from four lung cancer cells was smaller than 1. This synergistic antitumour effect was based on the increase of their single proapoptotic effect but inhibiting FC ‐induced autophagy in NCI ‐H460 cells. FC and PVII activated proapoptotic elements like cleaved‐caspase‐3, ‐8, and ‐9 to induce Beclin1 cleaved into Beclin1‐C which suppressed FC ‐triggered autophagy and enhanced apoptosis. Conclusions Formosanin C and PVII showed a synergistic antitumour effect on lung cancer cells. The findings would provide the foundation for the use of combination drugs in the future.

Polyphyllin VII suppresses cell proliferation, the cell cycle and cell migration in colorectal cancer

“…The results showed that polyphyllin VII could induce cancer cell apoptosis via regulating caspase protein activation in oral cancer (30). Several recent studies demonstrated that polyphyllin VII could induce the autophagy process in tumor cells (11,30,35). Distant metastasis is the primary cause of cancer-related deaths.…”

Molecular mechanisms of anticancer activities of polyphyllin VII

“…The PPGinduced apoptosis was confirmed through caspase inhibitor (z-VAD-FMK), which inhibits the cell PPG-induced apoptosis in HONE-1 and NPC-039 cells (Chen et al, 2016). Furthermore, the PPVII and formosanin induced apoptosis in NCI-H460 cell via inhibition of Bcl-2 and activation of Bax, caspase-3,9 (Cui & Man, 2019). The summarized form of mitochondrial-dependent pathway is depicted in Figure 2a.…”

Natural Polyphyllins (I, II, D, VI, VII) Reverses Cancer Through Apoptosis, Autophagy, Mitophagy, Inflammation, and Necroptosis

“…98 Pretreatment with Z-VAD-FMK (caspase inhibitor) on HepaRG cells increases the percentage of viable cells, indicating that PPVI induces cell apoptosis through the mitochondrial pathway and the Fas deathdependent pathway. 63 PPVII or PPG induces apoptosis in a dose-dependent manner in human NPC, 66 A549, 98 NCI-H1299, 98 HepG-2, 64 SAS, 91 and OECM-1 92 cells by upregulating the expression of DR3, 98 DR5, 98 Fas, 98 caspase-8, 64,66,91 cleaved PARP, 98 and cleaved caspase-3 64,66,91,98 but downregulating the expression of DcR3. 98 The summarized form of the extrinsic apoptotic pathway is depicted in Figure 1B.…”

“… 66 Formosanin C and PPVII increase apoptosis in NCI‐H460 cells by downregulating Bcl-2 and upregulating Bax, caspase-3, −8, and 9. 92 The summarized form of the mitochondrial-dependent pathway is depicted in Figure 1A .…”

“…90 PPVI in HepaRG cells induces MDP apoptosis through Bcl-2 downregulation and Bax upregulation, triggering cytochrome c release from the mitochondria and upregulating caspase-9,3 and PARP. 63 PPVII 66 or PPG 64,91 induces apoptosis in SAS, 91 OECM-1 92 , HepG-2, 64 and NPC 66 cells through downregulation of Bclxl 66,91 and Bcl2 64,66,91 and upregulation of Bak, 91 Bad, 64 Bax, 64,66 Bim, 91 and tBid 91 levels. This phenomenon causes cytochrome c 64 release from the mitochondria to the cytosol, which further increases the cleavage of caspase-3 64,66,91 and −9.…”