Natural Naphthohydroquinone Dimer Rubioncolin C Exerts Anti-Tumor Activity by Inducing Apoptotic and Autophagic Cell Death and Inhibiting the NF-κB and Akt/mTOR/P70S6K Pathway in Human Cancer Cells

Abstract

Naphthohydroquinone dimers isolated from Rubia plants have garnered more attention due to their distinctive chemical structures and intriguing bioactivities. In our previous studies, we obtained ten naphthohydroquinone dimers containing seven novel ones and found that most of them possessed anti-tumor activities, especially rubioncolin C. However, the underlying mechanism remains unknown. In this study, we focused on rubioncolin C and found that it could inhibit the growth of cancer cell lines with IC50 values between 1.14 and 9.93 μM. Further experiments demonstrated that rubioncolin C induced apoptotic and autophagic cell death and inhibited the Akt/mTOR/P70S6K signaling pathway in HCT116 and HepG2 cells. Moreover, we observed that rubioncolin C inhibited the TNF-α- and LPS-induced NF-κB activation upstream of the p65 protein, which contributed to rubioncolin C-induced cell death. Rubioncolin C could also prevent LPS-induced endotoxin shock in vivo. Moreover, rubioncolin C suppressed tumor growth through inducing apoptosis and autophagy and inactivating NF-κB in vivo. These findings clarify the anti-tumor mechanism of rubioncolin C using biochemical techniques and pharmacological models and might contribute to the future development of rubioncolin C as a new therapeutic agent for treating cancer.

Aggregation-Induced Emission Photosensitizer Synergizes Photodynamic Therapy and the Inhibition of the NF-κB Signaling Pathway to Overcome Hypoxia in Breast Cancer

“…The TPE-Py NPs were purified using a 0.22 μm millipore filter. The RC-loaded microemulsion was prepared as described previously …”

“…The yellow-emissive dye is characterized by a long emission wavelength and high quantum yield of fluorescence. TPE-Py has been used to visualize cells and structures, such as cancer cells, bacteria, and telomerase. , It also has been reported that the mitochondria-targeted TPE-Py has moderate anticancer activity against HeLa, Miapaca-2, A2780, PA-1, NTERA-2, BGC-823, and SGC-7901 cells. , RC is a plant-derived natural product isolated from Rubia plants that are widely used in traditional Chinese medicine. − Our previous studies demonstrated that RC is a potent mitochondrial destructor and has significant ROS-generating ability. , Moreover, RC suppresses cancer metastasis and causes apoptosis and autophagic cell death in TNBC by activating the MAPK and inhibiting both the NF-κB and mTOR/Akt/p70S6K pathways. , Therefore, we speculated that RC combined with TPE-Py not only inhibits OXPHOS and restores local oxygen levels to favor PDT but also triggers a severe ROS burst to ablate cancer. The NF-κB signaling pathway is the key regulator of prosurvival, embryogenesis, innate immune response, and anti-apoptosis, which is constitutively activated in many cancers. , Previous study has shown that the activation of the NF-κB signaling pathway plays a negative role in PDT .…”

“…30−34 Our previous studies demonstrated that RC is a potent mitochondrial destructor and has significant ROS-generating ability. 35,36 Moreover, RC suppresses cancer metastasis and causes apoptosis and autophagic cell death in TNBC by activating the MAPK and inhibiting both the NF-κB and mTOR/Akt/ p70S6K pathways. 35,36 Therefore, we speculated that RC combined with TPE-Py not only inhibits OXPHOS and restores local oxygen levels to favor PDT but also triggers a severe ROS burst to ablate cancer.…”

“…35,36 Moreover, RC suppresses cancer metastasis and causes apoptosis and autophagic cell death in TNBC by activating the MAPK and inhibiting both the NF-κB and mTOR/Akt/ p70S6K pathways. 35,36 Therefore, we speculated that RC combined with TPE-Py not only inhibits OXPHOS and restores local oxygen levels to favor PDT but also triggers a severe ROS burst to ablate cancer. The NF-κB signaling pathway is the key regulator of prosurvival, embryogenesis, innate immune response, and anti-apoptosis, which is constitutively activated in many cancers.…”

Zoopharmacology: A Way to Discover New Cancer Treatments

“…Other species of this genus have also attractive naphthohydroquinone compounds such as Rubioncolin C from Rubia podantha Diels, which inhibited AKT/mTOR/p70S6K signaling pathway and NF-κβ factor inducing apoptosis and autophagy in HCT116 and HepG2 cell lines [ 55 ].…”