Combination of Tanshinone IIA and Cisplatin Inhibits Esophageal Cancer by Downregulating NF-κB/COX-2/VEGF Pathway
Authors: Lanting Tao
Ying Gao
Jun Xie
Jiahui Liu
Suilin Mo
Dongmei Wang
Xiaozhong Liao
Yueyu Gu
Taoli Liu
Dan Xie
Journal: Frontiers in Oncology (2020)
Discipline: CLINICAL MEDICINE
Keywords: DDP; ESCC; NF-κB/COX-2/VEGF pathway; Tan IIA; synergistic effect.
Affiliations: Department of Traditional Chinese Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China., State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China., Department of Oncology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China., Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China., The Second Clinical College, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China., The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China., School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.

Abstract:  Cisplatin (DDP) represents one of the common drugs used for esophageal squamous cell carcinoma (ESCC), but side effects associated with DDP and drug resistance lead to the failure of treatment. This study aimed to understand whether tanshinone IIA (tan IIA) and DDP could generate a synergistic antitumor effect on ESCC cells. Tan IIA and DDP are demonstrated to restrain ESCC cell proliferation in a time- and dose-dependent mode. Tan IIA and DDP at a ratio of 2:1 present a synergistic effect on ESCC cells. The combination suppresses cell migration and invasion abilities, arrests the cell cycle, and causes apoptosis in HK and K180 cells. Molecular docking indicates that tan IIA and DDP could be docked into active sites with the tested proteins. In all treated groups, the expression levels of E-cadherin, β-catenin, Bax, cleaved caspase-9, P21, P27, and c-Fos were upregulated, and the expression levels of fibronectin, vimentin, Bcl-2, cyclin D1, p-Akt, p-ERK, p-JNK, P38, COX-2, VEGF, IL-6, NF-κB, and c-Jun proteins were downregulated. Among these, the combination induced the most significant difference. Our results suggest that tan IIA could be a novel treatment for combination therapy for ESCC. 

Retracted: No

PubPeer comments:
 Two images in Figure 3B appear to overlap. *** ![file] , 
 Thank you very much for your reminding. Our research group immediately checked the original data of the experiment. We are very sorry for the mistake caused by a mistake in the process of arranging the pictures. We have send Editorial Office the original experiment pictures together with the corrected pictures. Thank you again for your rigor. , 
 #2 I thank the author for promptly responding. I have identified other possible irregularities in this paper. The flow cytometry plots show areas of close similarity as well as areas of difference, which may not be explained by an error during figure assembly. *** ![file] ![file] , 
 As the apoptosis experiment results are stored on the flow cytometry instrument platform and the lab regularly clears the computer memory, we cannot find the original experimental data at present.For the occurrence of this situation, we understand that it may be the same kind of cell, the same cell size and shape caused by.In order to ensure the accuracy of the experimental results, we plan to conduct the apoptosis experiment again to confirm the experimental results again.At that time, we will contact the editorial department of the journal.Thanks again for your criticism and correction. I really appreciate it. , 
 As the first corresponding author, I really appreciate your comments on our research. We are very sorry for the mistakes we made in sorting out the experimental results. We immediately carried out self-examination of the whole study and contact the editorial department of the journal to correct any mistakes. Thank you again for your generous help. , 
 I greatly appreciate your interest and comments on our paper. As the co-corresponding author, I have made them our highest priority and immediately re-examined our original data very carefully once I received the comments. We are so sorry for the mistakes made in this paper. We will contact editorial office to correct the mistakes as soon as possible. Thank you again for your valuable comments. , 
 #4 Very disappointed that the original data was not safely retained given that this is a recent paper. Do your funding agencies require records to be maintained? *** ![file] , 
 #4 Note that the identical points within pairs of scatterplots are more confined to the lower-left quadrant, though they are more noticeable there. Here I have superimposed the HK-Control and HK-TanIIA panels, color-reversing the latter so that identical points cancel out. Dark points are unique to Control; light points are unique to TanII. ![file] The same treatment applied to K180-Control and K180-TanIIA: ![file] * For the occurrence of this situation, we understand that it may be the same kind of cell, the same cell size and shape caused by * Using the same kind and size and shape of cell will not cause an identical area of points (cell measurements) to appear within two flow-cytometry plots. It is more likely that two images were plotted from **the same raw data**, differently filtered. , 
 This paper is one of a small collection of papers which appears to include a typographical error in the spelling of an manufacturer. The company name is ACEA Biosciences headquartered in San Diego. In this paper and the others, the name is spelled ACEC. This suggests that the paper was written from a common template, although the author groups are mostly different. *** ![file] , 
 #4 For a paper published in Sep 2020 it unfortunate not to find the original FACS data, if I may say so. Further, as already explained for similar cases: It is **highly unlikely** that such FACS plot irregularities as they are shown in #3 are du to  sample contamination or  similar cells or  same shaped cells - unless you analyze perfect spheres with 100% identical fluorochrome labeling in flow cytometry. Even measuring the same sample twice won t give you an identical dot pattern. Please consider that. , 
 Does anyone with experience with these Novocyte Novoexpress combinations know what the first digit denotes in the quadrant labels? Is it data set? ![file] , 
 I would also note for other readers that this group appears to have more than a [dozen papers] with similar concerns. , 
 Corrigendum [6 April 2021] . --------------------------------------------------- There is an error in the Funding Statement. The correct funder and grant should be  National Natural Science Foundation of China (grant No. 81602063) . In the original article, there was a mistake in Figures 3B and 5A as published. For would-healing assay in Figure 3B, the u201cDDP groupu201d image of K180 cell line was misused. We re-checked the raw data and found these mislabeled images during the picture layout. For apoptosis assay in Figure 5A, after we examined the original data, we found that we were setting the parameter conditions and setting the gate incorrectly, which led to this misunderstanding. In order to avoid causing unnecessary misunderstanding, we found the original file and re-exported the experiment images. And we apply to replace these experimental results together. The corrected Figures 3 and 5 appear below. ![] ![] The following authors did not fulfil the authorship criteria and need to be removed from the author list: Jun Xie, Yueyu Gu and Taoli Liu. English revisions are not considered an authorship criterion and therefore the authors stated above must be removed from the author list, and author contributions and included in the Acknowledgments section. In the original article, there was an error. We incorrectly wrote the FCM instrument name ACEA as ACEC. A correction has been made to the Material and Method, sections Flow Cytometric Cell Cycle Analysis and Apoptosis Assay and Acknowledgment. ACEA NovoCyte flow cytometer equipped with Novoexpress (Becton Dickinson, San Jose, CA, USA) was applied to detect the cell cycle. ACEA NovoCyte flow cytometer equipped with Novoexpress (Becton Dickinson, San Jose, CA, USA) was applied to detect cell apoptosis. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated. , 
 Now retracted. u201cFollowing publication, concerns were raised regarding the integrity of the images in the published figures. The authors failed to provide a satisfactory explanation during the investigation, which was conducted in accordance with Frontiersu2019 policies. This retraction was approved by the Chief Editors of Frontiers in Oncology and the Chief Executive Editor of Frontiers. The authors did not agree to this retraction. ,