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

Jia Wang,Ninghua Tan,Jing Wang,Ling Li,Lihua Song,Zhe Wang

doi:10.3390/cells8121593

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.

Highlights

Plant-derived natural products with unique skeletons and various bioactivities, a rich source of privileged structures, drug leads and candidates, have played an irreplaceable role in drug discovery over the centuries, such as morphine, taxol, and artemisinin [1,2,3]
We firstly reported the novel finding that rubioncolin C (RC) could inhibit tumor cell growth in vitro and in vivo and induce apoptotic and autophagic cell death through inhibiting the nuclear factor κB (NF-κB) and Akt/mTOR/P70S6K signaling pathways, which would contribute to the future development of RC as a new therapeutic agent for treating cancer
The roots and rhizomes of several Rubia plants have been widely used for the treatment of cancer, menoxenia, rheumatism, and tuberculosis, especially R. cordifolia, which was recorded as a traditional Chinese medicine in all editions of Chinese Pharmacopeia

Summary

Introduction

Plant-derived natural products with unique skeletons and various bioactivities, a rich source of privileged structures, drug leads and candidates, have played an irreplaceable role in drug discovery over the centuries, such as morphine, taxol, and artemisinin [1,2,3]. Quinones, including benzoquinones, naphthoquinones, phenanthraquinones and anthraquinones, widely exist in medicinal plants and exhibit various bioactivities, and some of their derivatives have been used in clinical therapy, such as mitoxantrone for anti-metastatic breast cancer, idebenone for anti-Alzheimer’s disease, and atovaquone for anti-pneumonia [4]. Naphthohydroquinone dimers have drawn more attentions for their distinctive chemical structures and intriguing bioactivities [5]. 17 naphthohydroquinone dimers have been isolated from Rubia plants [5,11,12,13,14,15,16,17] (Figure S1), and some of. Cells 2019, 8, 1593 them have been synthesized totally [18,19,20] These isolated compounds possessed anti-tumor activities, rubioncolin C (RC) (Figure 1A)

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Conclusion