Mahanine induces apoptosis, cell cycle arrest, inhibition of cell migration, invasion and PI3K/AKT/mTOR signalling pathway in glioma cells and inhibits tumor growth in vivo
Authors: Chuan Lu
Xiandong Chen
Jun Sun
Jianyong Cai
Xiangqian Yin
Huajun Ba
Maohua Chen
Journal: Chemico-Biological Interactions (2019)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: Apoptosis; Glioma; Invasion; Mahanine; PI3K/AKT.
Affiliations: Department of Neurosurgery, Wenzhou Central Hospital, Affiliated Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, 325000, China., Department of Oncology, Wuhan Huangpi People's Hospital, 430300 , Wuhan, China., Department of Neurosurgery, Wenzhou Central Hospital, Affiliated Dingli Clinical Institute of Wenzhou Medical University, Wenzhou, 325000, China. Electronic address: .

Abstract:  Gliomas are among the most frequent types of primary malignancies in the central nervous system. The main treatment for glioma includes surgical resection followed by a combination of radiotherapy and chemotherapy. Despite the availability of several treatments, the average survival for patients with glioma at advanced stages still remains 16 months only. Therefore, there is an urgent need to look for novel and more efficient drug candidates for the treatment of glioma. In the current study the anticancer activity of Mahanine was evaluated against a panel of glioma cells. The results revealed that Mahanine exerted significant anticancer effects on the glioma HS 683 cells with an IC50 of 7.5 μM. However, the cytotoxic effects were less pronounced on the normal human astrocytes. Further the results showed that the anticancer effects were mainly due to induction of apoptosis and G2/M cell cycle arrest. Western blotting showed that Mahanine caused upregulation of Bax, cytochrome c, cleaved caspase 3 and 9 and cleaved PARP. However, the expression of cell cycle related proteins pCdc25c, Cdc25c, pCdc2, Cdc2 and cyclin B1 was significantly downregulated. The effect of Mahanine on the migration and invasion of HS 683 cells was also determined and results indicated that Mahanine inhibited the cell migration and invasion at IC50. Additionally, Mahanine-inhibited cell growth was simultaneous with suppression of p-PI3K, p-AKT and p-mTOR. Taken together these results indicate that Mahanine may prove to be an important lead molecule for the treatment of glioma and warrants further investigation. 

Retracted: No

PubPeer comments:
 *[left]* Fig 3B,C. *[right]* Fig 5 from [Zhang, Li Ji (2018)] . ![file] , 
 Fig 1C. ![file] For comparison, Fig 3 from [Zhang, Li Ji (2018)] , and Figure 1C from [Huang, Xie Liu (2019)] . ![] , 
 #1 *[right]* Fig 3B,C from [Chen et al (2019)] . *[left]* Figure 7 from [Zhang et al (2018)] .  Effect of 0, 20, 40 and 80 u00b5M 23,24-dihydrocucurbitacin B on the expression of mTOR PI3K Akt signaling pathway proteins in HeLa cells . ![file] I have concerns. , 
 *[left]* Fig 1(E) from [Chen et al (2019)] .  AO EB staining for apoptosis . *[right]* Figure 4 from [Li et al (2018)] .  AO EB staining showing induction of apoptosis in AMC-HN-8 cells upon treatment with Mukonal . ![file] , 
 *[left]* Figure 1D from [Chen et al (2019)] .  Antiproliferative effects of Mahanine on Glioma HS 683 cells. ... (D) DAPI staining showing apoptotic 378 cells . *[right]* Fig 2 from [Zhang et al (2018)] .  Ludartin triggered apoptosis in Saso-2 osteosarcoma cells. Apoptosis was studied by fluorescence-activated cell sorting (FACS) using 4u2019, 6-diamidino-2-phenylindole (DAPI) nuclear staining. ![file] Other appearances are linked in that other thread. , 
 #4 *[left]* Fig 1(E) from [Chen et al (2019)] .  AO EB staining for apoptosis . *[middle]* Figure 4 from [Li et al (2018)] .  AO EB staining showing induction of apoptosis in AMC-HN-8 cells upon treatment with Mukonal . *[right]* Fig 2C,D from [Du et al (2020)] .  DAPI staining of miR-NC and miR-143 mimics transfected CAMA-1 cells. ...  AO EB staining of miR-NC and miR-143 mimics transfected CAMA-1 cells . ![file] UPDATE: A fourth sighting! Fig 3C from [Jun et al (2018)] .  Suppression of lncRNA UCA triggers apoptosis in NCI-H23 lung cancer cells... (C) AO EB staining . ![] , 
 *[left]* Fig 4B from [Chen et al (2018)] .  Mahanine treatment for 24 h inhibits cell migration and invasion of Glioma HS 683 cells. ... cell invasion assay . *[middle]* Fig 2C from [Jun et al (2018)] .  Effect of suppression of lncRNA UCA1 on cell invasion . *[right]* Figure 4A from [Wang Wen (2020)] .  miR-335 reduces breast cancer cell migration and invasion. A: Transwell assay for analysis of migration and invasion of Hs578T cancer cells transfected with miR-NC, miR-335 mimics or miR-335 inhibitor showing miR335 overexpression inhibits cell migration and **invasion** . Rotated through 90 deg for convenience of comparison. ![file] , 
 #2 Fig 1C again: ![] ImageTwin informs me that the panels were taken from Fig 2 of  PC3 prostate tumor-initiating cells with molecular profile FAM65Bhigh MFI2low LEF1low increase tumor angiogenesis ([Zhang Waxman 2010] ). ![file] , 
 #5 *[left]* Fig 1D again. The source turns out to be *[right]* Fig 6A-E from  Using the u201ctarget constituent removal combined with bioactivity assayu201d strategy to investigate the optimum arecoline content in charred areca nut ([Peng et al 2017] ). ![file] , 
 - *[left]* Fig 6 from  Anticancer Activity of Phloretin Against Human Gastric Cancer Cell Lines Involves Apoptosis, Cell Cycle Arrest, and Inhibition of Cell Invasion and JNK Signalling Pathway ([Xu et al 2018] ). - *[right] **Fig 4**. ![file] ,