Regulation of anti-tumour effects of Paris polyphylla saponins via ROS: molecular mechanisms and therapeutic potentials

Abstract

Reactive oxygen species (ROS) exhibit a dual regulatory role in cancer biology. While moderate ROS levels promote tumorigenesis via DNA mutagenesis, excessive ROS accumulation induces cancer cell death through oxidative stress. Therefore, ROS homeostasis represents a promising therapeutic target in oncology. Collectively, ROS exhibit context-dependent and multifaceted roles in cancer progression. Emerging evidence highlights the anticancer potential of traditional Chinese medicine (TCM), particularly Paris polyphylla saponin (PPS). PPS modulates oxidative stress through precision targeting of ROS-associated signaling pathways, thereby inducing apoptosis, cell cycle arrest, autophagy, and ferroptosis. These mechanisms collectively suppress tumor growth, metastasis, and angiogenesis, while concurrently mitigating inflammatory responses. Notably, PPS potentiates the efficacy of chemotherapeutic agents by reversing multidrug resistance in refractory cancer cells. The bioactive constituents of PPS, polyphyllin and polyphyllinositol, exhibit potent antitumor activity in preclinical models. This study systematically elucidates the molecular mechanisms underlying PPS-mediated anticancer effects via ROS targeting, offering a robust theoretical framework and translational insights for future oncology research.

Keywords: Paris polyphylla; anti-cancer; mechanism; reactive oxygen species; saponins.

FIGURE 1

Rhizoma Paridis and its anti-cancer bioactive ingredients Rhizoma Paridis saponins (RPS). Commercially available RPS include polyphyllin I/polyphyllin D, polyphyllin II, Dioscin, polyphyllin V, polyphyllin VI, polyphyllin VII, polyphyllin B, polyphyllin C, polyphyllin E, polyphyllin F, and polyphyllin H.

FIGURE 2

Main generation and modulation of ROS.ROS are primarily generated by mitochondria and cellular membrane NOXs, and their metabolism is regulated by multiple mechanisms. SOD converts O₂·^- into H₂O₂. H₂O₂ has two metabolic fates: ① it can react with Fe²⁺ through the Fenton reaction to produce hydroxyl radical (OH·), resulting in oxidative injury to cellular macromolecules such as DNA, proteins, and lipids; ② it can be reduced to water by the antioxidant system composed of PRXs, GPXs, and CAT, thereby regulating the intracellular oxidative balance.

FIGURE 3

Effects of ROS on cells: physiological function, cancer development, and cell demise.In normal cells, ROS production, antioxidant responses, and cellular repair processes are tightly balanced, maintaining ROS at optimal levels to restrict excessive cell persistence and multiplication. Elevated ROS concentration can induce cellular harm; however, tumor cells often exhibit increased antioxidant capacity and adapt through metabolic reprogramming and hypoxia-induced signaling pathways, supporting tumor-promoting effects. Nevertheless, when ROS surpass a critical threshold, oxidative stress causes irreversible cellular damage, overwhelms adaptive mechanisms, and ultimately triggers tumor cell death.

FIGURE 4

As signaling molecules, ROS participate in the PI3K/Akt/mTOR and MAPK/ERK pathways, modulate NF-κB activity, and are associated with Nrf2 mutations. By inhibiting PHD2 and stabilizing HIF-1α, ROS facilitate tumor cell motility and invasiveness.HIF-1α activation induces the expression of lactate dehydrogenase and pyruvate dehydrogenase kinase 1, suppresses antioxidant genes involved in GSH metabolism, and reduces mitochondrial ROS production, thereby promoting extracellular matrix degradation and invasive behavior. Furthermore, HIF-1α-driven signaling facilitates VEGF-mediated angiogenesis, while ROS accelerate tumor metastasis through MMP-mediated breakdown of ECM proteins, enhancing both vascularization and metastatic spread.

FIGURE 5

ROS mediate antitumor effects by triggering RCD pathways, including apoptosis, autophagy, necroptosis, and ferroptosis. ROS act on the MPTP, reducing the mitochondrial membrane potential (MMP), which prompts the release of Cyt-c into the cytoplasm, where it binds to APAF-1 and procaspase-9, initiating the caspase-9 cascade reaction and triggering apoptosis.The ROS also enhance the extrinsic apoptosis pathway by degrading c-FLIP and activate RIP1 and RIP3 to induce necroptosis. ROS inactivate the autophagy-related gene Atg4, increase LC3-associated autophagosomes, and promote autophagy, while the inhibition of mTORC1 and the activation of AMPK negatively regulate autophagy. Ferroptosis is an ROS-driven, iron-dependent form of programmed cell death characterized by lipid peroxidation. The Fenton reaction enhances the activity of lipoxygenase and the production of ROS. Erastin disrupts the XC− system, damaging the GPX antioxidant mechanism.Elevated ROS levels disrupt the integrity of the outer mitochondrial membrane, while RSL3 induces ferroptosis by suppressing GPX activity.

FIGURE 6

Polyphyllin triggers apoptosis and autophagy for cancer treatment by regulating reactive oxygen species levels. Paradisaponin increases intracellular ROS levels, triggering oxidative stress, which in turn activates endogenous and exogenous apoptosis pathways, leading to the death of cancer cells. It can elevate ROS levels in the mitochondria and cytoplasm, resulting in a decrease in mitochondrial membrane potential, the release of cytochrome c, and the subsequent activation of the Caspase cascade system, leading to PARP cleavage and DNA fragmentation, ultimately triggering apoptosis. Paradisaponin, by increasing ROS levels, inhibits the AKT/mTOR pathway, activates the AMPK and MAPK pathways to promote LC3-II expression, and induces autophagy in cancer cells.

FIGURE 7

Polyphyllin exerts anticancer effects by inducing ROS-mediated cell cycle arrest in cancer cells. Polyphyllin increases ROS levels to activate the PI3K/Akt signaling cascade and JNK/NF-κB, leading to cell cycle arrest at the G0/G1 and G1 phases The upregulation of p53 promotes the expression of p21, which inhibits CDK2-cyclin complexes and proliferating cell nuclear antigen (PCNA), thereby blocking G1/S phase transition and inducing S phase arrest. Additionally, Polyphyllinsuppresses cyclin B1 expression, disrupting the CDK1-cyclin B1 complex and resulting in G2/M phase arrest.