Esophageal squamous cell carcinoma (ESCC) is among the most common malignancies worldwide and the fourth leading cause of cancer-related death in China. It is an aggressive disease with a poor prognosis and is unresponsive to most conventional chemotherapeutic agents. Plumbagin (5-hydroxy-2-methyl-1,4-napthoquinone) is a “natural quinoid constituent isolated from the roots of the medicinal plant Plumbago Zeylanica L.” Although Plumbagin has exhibited significant anti-cancer activity in various human cancers including cancer of the lungs, breast, ovary, prostate, and colon, its potential antitumoral efficacy on ESCC remains to be determined.
Researchers led by Professor Yu Zhang from the State Key Laboratory of Molecular Oncology-National Cancer Center/Cancer Hospital at Chinese Academy of Medical Sciences & Peking Union Medical College evaluated the potential antitumor effects of the Plumbagin against ESCC cells both in vitro and in vivo, as well as the underlying mechanisms of these effects in ESCC cells. Their research work was published in the journal Cell Death & Disease.
The authors observed that plumbagin inhibited the cell proliferation in two independent ESCC cell lines, KYSE150 and KYSE450, in concentration-dependent and time-dependent manner. The IC50 values of plumbagin in KYSE150 and KYSE450 cells were 6.4 ± 0.2 and 8.0 ± 0.3 μM, respectively.
The research team also performed chemosensitivity assay using primary cultured ESCC cells and results indicated that most of specimens responded well to the drug. Notably, when compared to two drugs currently used in ESCC chemotherapy, 5-Fu and Cisplatin, the IC50 and IC90 of plumbagin were markedly lower indicating that plumbagin is more effective compared to either 5-Fu or DDP in these cases.
Moreover, they found that plumbagin induced cell cycle arrest and apoptosis in ESCC cells. The colony formation capacity of ESCC cells was also suppressed by plumbagin. Furthermore, they found that intraperitoneal administration of plumbagin drastically reduced the growth of subcutaneous KYSE150 xenograft in nude mice. Of note, the plumbagin treatment showed no apparent systemic toxicity in vivo as evidenced by no observable weight loss during the experimental period.
Since the results of the research team showed that inhibition of polo-like kinase 1 (PLK1) led to G2/M cell cycle arrest and apoptosis that were identical to the phenotypes elicited by plumbagin in ESCC cells, the authors tried to linked the mechanism of action of the drug to PLK1. Indeed, their results showed that plumbagin potentiated ESCC cells apoptosis through downregulation of PLK1 expression. By downregulating PLK1, plumbagin inactivated AKT. Lastly, STAT3, a transcriptional factor of PLK1, is involved in the plumbagin-mediated blockade of PLK1-AKT cascade. The data from the study suggested that plumbagin downregulated PLK1 mRNA expression by abrogating the activity of STAT3 in ESCC cells.
Overall, the results suggested that plumbagin is a potential and promising anti-cancer drug for treatment of ESCC.
Dr. Yu Zhang
She received a B.S. degree in Department of Biology at Harbin Normal University, Harbin, China, in 1995 and completed her Ph.D. degree in Laboratory of Medical Genetics and Cell Biology at Harbin Medical University, Harbin, China, in 2003. From 2003 to 2005, She did her postdoctoral study with Professor Ming-Rong Wang in State Key Laboratory of Molecular Oncology at National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS & PUMC). In 2006, She joined the faculty in State Key Laboratory of Molecular Oncology at CAMS & PUMC. Since 2010, she has been appointed as an associate Professor of National Cancer Center/Cancer Hospital at CAMS & PUMC.
Research in Dr. Zhang’s laboratory focuses on investigation of the function and related molecular mechanism of tumor associated genes, identification of cancer biomarkers and discovering novel therapeutic targets, and exploration of effective therapeutic strategies for the treatment of malignant tumors, especially colorectal cancers (CRC) and esophageal squamous cell carcinoma (ESCC).
Cao, Y., Yu, J., Liu, T., Yang, K., Yang, L., Chen, Q., Shi, F., Hao, J., Cai, Y., Wang, M., Lu, W., Zhang, Y. Plumbagin inhibits the proliferation and survival of esophageal cancer cells by blocking STAT3-PLK1-AKT signalling. Cell Death and Disease (2018) 9:17