Paclitaxel and Cephalomannine Synergistically Induce PANoptosis in Triple-Negative Breast Cancer Through
Xinyu Gao1,2, Kuilin Chen1,2, Shuhui Jia1,3
1State Key Laboratory of Chemical Oncogenomics, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China.
Abstract:
Triple-negative breast cancer (TNBC) urgently requires new therapeutic strategies due to the limited efficacy of conventional treatments. Recently, PANoptosis, an integrated form of apoptosis, necroptosis, and pyroptosis, has emerged as a promising target in cancer therapy, though effective agents remain scarce. Paclitaxel, a Taxus-derived natural product, is often combined with other drugs to enhance efficacy, yet optimal combinations are limited. This study investigates the synergistic antitumor effects of paclitaxel and cephalomannine in TNBC, focusing on oxygen-regulated cell death pathways. Network pharmacology and molecular docking revealed that the combination targets multiple cell death- and inflammation-related proteins, including BCL2L1, MAPK14, SYK, TNF, and ADAM17, suggesting multi-target synergy. In vitro, the combination significantly inhibited MDA-MB-231 cell viability, proliferation, and migration, while inducing apoptosis and necrosis. Mechanistically, co-treatment markedly increased intracellular ROS levels and γ-H2AX expression, indicating oxidative stress and DNA damage, both of which were reversible by ROS inhibition. Further analysis demonstrated that the treatment activated the p38 and p53 pathways, regulated the Bax/Bcl-2 ratio, and initiated mitochondrial apoptosis. It also promoted RIPK1/RIPK3/MLKL phosphorylation and MLKL membrane translocation, triggering necroptosis, as well as upregulated NLRP3, cleaved Caspase-1, and GSDMD, inducing pyroptosis. The use of specific inhibitors partially reversed these effects, confirming the involvement of ROS-mediated PANoptosis. Similar antitumor effects were also observed in BT-549 cells, indicating the broad applicability of this combination in TNBC. MCF-10A cells exhibited mild but acceptable cytotoxicity, reflecting manageable side effects typical of chemotherapeutic agents. In vivo experiments further validated the combination's antitumor efficacy and safety. In summary, paclitaxel and cephalomannine synergistically induce PANoptosis in TNBC through oxygen-regulated cell death pathways, offering a novel therapeutic strategy based on oxidative stress modulation by natural compounds.
Insights
Paclitaxel and cephalomannine synergistically combat triple-negative breast cancer by inducing PANoptosis, a programmed cell death pathway. This natural compound combination offers a novel therapeutic strategy targeting oxidative stress and multiple cell death mechanisms.
Area of Science:
- Oncology
- Pharmacology
- Cell Biology
Background:
- Triple-negative breast cancer (TNBC) lacks effective treatments, necessitating novel therapeutic strategies.
- PANoptosis, a regulated cell death pathway, presents a promising target for cancer therapy.
- Paclitaxel is a common chemotherapy agent, but its efficacy is often limited, requiring combination therapies.
Purpose of the Study:
- To investigate the synergistic antitumor effects of paclitaxel and cephalomannine in TNBC.
- To elucidate the underlying mechanisms involving oxygen-regulated cell death pathways.
- To evaluate the therapeutic potential of this combination for TNBC treatment.
Main Methods:
- Network pharmacology and molecular docking were used to identify potential synergistic targets.
- In vitro studies assessed cell viability, proliferation, migration, apoptosis, and necrosis in TNBC cell lines.
- Mechanistic studies involved analyzing reactive oxygen species (ROS) levels, DNA damage, and key proteins in apoptosis, necroptosis, and pyroptosis pathways.
- In vivo experiments evaluated the antitumor efficacy and safety of the combination.
Main Results:
- The paclitaxel-cephalomannine combination demonstrated synergistic inhibition of TNBC cell viability, proliferation, and migration.
- Co-treatment induced significant apoptosis, necrosis, and PANoptosis by increasing ROS and DNA damage.
- The combination activated p38, p53, RIPK1/RIPK3/MLKL, and NLRP3 inflammasome pathways, leading to programmed cell death.
- In vivo studies confirmed the combination's potent antitumor activity and favorable safety profile.
Conclusions:
- Paclitaxel and cephalomannine synergistically induce PANoptosis in TNBC via ROS-mediated oxygen-regulated cell death pathways.
- This combination represents a novel therapeutic strategy for TNBC, modulating oxidative stress with natural compounds.
- The findings support the clinical investigation of paclitaxel and cephalomannine as a combined therapy for TNBC.
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