Œ≤-Sitosterol and Gemcitabine Exhibit Synergistic Anti-pancreatic Cancer Activity by Modulating Apoptosis and Inhibiting Epithelial‚ÄìMesenchymal Transition by Deactivating Akt/GSK-3Œ≤ Signaling
Authors: Xiao-Bin Li
Yan Wang
Guang-Ru Zhang
Zhan-Jun Ma
An-Chen Shi
Zhang-Qi Cao
Li Lu
Xue-Xi Wang
Yu-Jun Song
Jing-Wen Xu
Journal: Frontiers in Pharmacology (2019)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: AKT; EMT; GSK-3Œ≤; apoptosis; gemcitabine
Affiliations: School of Basic Medical Sciences, Lanzhou University, Lanzhou, China., Qinghai Hospital of Traditional Chinese Medicine, Xining, China., The Second Clinical School, Lanzhou University, Lanzhou, China.

Abstract:  Œ≤-sitosterol (BS), a major bioactive constituent present in plants, has shown potent anti-cancer activity against many human cancer cells, but its activity in pancreatic cancer (PC) cells has rarely been reported. Gemcitabine (GEM) is one of the first-line drugs for PC therapy, however, the treatment effect is not sustained due to prolonged drug resistance. In this study, we firstly studied the anti-PC activity and the mechanism of BS alone and in combination with GEM in vitro and in vivo. BS effectively inhibited the growth of PC cell lines by inhibiting proliferation, inducing G0/G1 phase arrest and apoptosis, suppressed the NF- kB activity, and increased expression of the protein Bax but decreased expression of the protein Bcl-2. Moreover, BS inhibited migration and invasion and downregulated epithelial-mesenchymal transition (EMT) markers and AKT/GSK-3Œ≤ signaling pathways. Furthermore, the combination of BS and GEM exhibited a significant synergistic effect in MIAPaCa-2 and BXPC-3 cells. More importantly, the combined treatment with BS and GEM lead to significant growth inhibition of PC xenografts. Overall, our data revealed a promising treatment option for PC by the combination therapy of BS and GEM. 

Retracted: No

PubPeer comments:
 Two images in figure 3A appear to overlap. Roughly marked with red boxes. ***  ***  , 
 Figure 7A and 7D appear to have two images which overlap. Roughly identified with green boxes. ***  , 
 https: imgur.com a dLcqQ3j , 
 #1 Dear Dr Biskrensis, Thanks very much for your kind attention and pointing out the problems in our article. We will seriously check and verify the pictures and original data of the article and actively contact with editors of the magazine. But because of the affection of the pandemic COVID-19, the checking process may be slower. We will make a reply about this. Thank you for your comments. , 
 #2 Dear Dr Biskrensis, Thanks very much for your kind attention and pointing out the problems in our article. We will seriously check and verify the pictures and original data of the article and actively contact with editors of the magazine. But because of the affection of the pandemic COVID-19, the checking process may be slower. We will make a reply about this. Thank you for your comments. , 
 #3 Dear Dr Dschang, Thanks very much for your kind attention and pointing out the problems in our article. We will seriously check and verify the pictures and original data of the article and actively contact with editors of the magazine. But because of the affection of the pandemic COVID-19, the checking process may be slower. We will make a reply about this. Thank you for your comments. , 
 #1 Dear Dr. Biskrensis, thank you for your comments. These comments are very important to us. We must apologize for our inadvertent mistakes. After carefully re-checked the raw data of Figure 3A, we found that the correct picture of the treatment of 125 u03bcmol L BS for BXPC-3 was overlapped by the picture of the treatment of 250 u03bcmol L BS for BXPC-3 during using the Photoshop software. Now, we have corrected, and we will contact with the journal to make a correction. We are very sorry that we didnu2019t realize these mistakes in time because of our careless. We sincerely apologized for making these severe mistakes. Meanwhile, thank you very much for your concerns about our article. I m looking forward to hearing from you at your earliest convenience. Thank you again for your hard work. Yours sincerely, Xuexi Wang.  , 
 #2 Dear Dr. Biskrensis, thank you for your comments. The comments are very important to us. We must apologize for our unintentional mistakes. After carefully re-checked the corresponding raw data, we found that the 7A picture of migration in BS+GEM group and 7D picture in BS group of BXPC-3 cell in published version were not consistent with our raw data in PowerPoint. Besides, we also found that the GEM group of Figure 7A of Mia-PaCa-2 and BS+GEM group in Figure 7D of Mia-PaCa-2 was not consistent with our raw data in PowerPoint. These mistakes are due to the careless of the combination photos in PowerPoint and Photoshop software, we are very sorry and regret about these serious mistakes. Now, we have revised these to the correct version of raw data, and we will contact with the journal to make a correction. We are very sorry that we didnu2019t realize these mistakes in time because of our careless. We sincerely apologized for making these severe mistakes. Meanwhile, thank you very much for your concerns and reminding. I m looking forward to hearing from you at your earliest convenience. Thank you for your hard work. Best regards, Xuexi Wang.  , 
 #3 Dear Dr. Dschang, thank you for your comments, and we must apologize for our inadvertent mistakes. After carefully re-checked the raw data of Figure 7D, we found that the correct picture of the control for BXPC-3 about invasion was overlapped by the picture of the control of migration for BXPC-3 during using of PowerPoint software. Now, we have revised this result. We sincerely apologized for making this mistake. Thank you again for your criticism and reminding. Best regards, Xuexi Wang.  , 
 A correction was published November 20, 2020. However, as can be seen from the annotated excerpts below, the corrected figures still appear to include multiple areas of overlap. Could the authors please review these images? 9 19 2020 ***  ,