Programmed cell death mechanisms of traditional plant medicine in prostate cancer therapy

Prostate cancer (PCa) is a prevalent malignancy in males with high morbidity and mortality. Although treatment modalities have evolved considerably, tumor resistance, recurrence, and metastasis persist, urgently requiring the exploration of alternative therapies for PCa. There is ongoing research on finding and identifying the use of traditional plant medicine (TPM). Cellular homeostasis comprises a sophisticated network of metabolic processes that functions cooperatively to preserve a stable intracellular environment. Programmed cell death (PCD) plays an important role in PCa mechanism. Thus, they represent an effective strategy for targeting PCa. TPM has been proven to induce PCD through multiple pathways and target in the treatment of PCa. Recent reviews have only focused on the one of the PCD, and autophagy, apoptosis, pyroptosis, ferroptosis, and necroptosis are not simultaneously reviewed.

The search strategy: articles with the title containing "prostate cancer", "therapeutic", "traditional medicine", "apoptosis", "pyroptosis", autophagy", "in vivo/in vitro", "active ingredients", "Herbal", "real modules", "dose", "pathway", "effects/mechanisms", "extract", "pure compound", "drug type", "anticancer activity", "Chinese herbal compounds", "necroptosis" and "ferroptosis" had been initially selected in the past five years databases of PubMed, Web of Science, and ScienceDirect. The references were screened according to the strategy.

Forty-two drugs in the TPM have been chosen in this review. The plant extract, Chinese herbal compound, and pure compound of TPM exhibit significant anticancer activity against PCa by regulating multiple kinds of PCD. More importantly, PI3K/AKT/mTOR, AMPK/mTOR pathways, AKT1/Bcl2/NF-κB, GPBAR1/NF-κB, Keap1/Nrf2/ARE, PINK1/Parkin signaling pathways serve as critical molecular targets mediating the anticancer activities of TPMs in PCD. Autophagy, apoptosis, and ferroptosis are research hotspots, while pyroptosis and necroptosis are less explored. Apoptosis is co-detected with autophagy, or necroptosis. Ferroptosis is co-detected with necroptosis, or pyroptosis. Notably, the interrelationships between these cell death modes are rarely investigated in depth in the treatment of TPM in PCa. TPM has been induced apoptosis, ferroptosis, necroptosis in PCa. But the effect of TPM on the autophagy and pyroptosis need further evidence to clarify the mechanism.

Hence, it is imperative to focus on elucidating the role of PCD modulators to refine therapeutic strategies of TPM in PCa.