Mahanine synergistically enhances cytotoxicity of 5-fluorouracil through ROS-mediated activation of PTEN and p53/p73 in colon carcinoma.
5-Fluorouracil (5-FU) alone or in combination with other drugs is the main basis of chemotherapeutic treatment in colorectal cancer although patients with microsatellite instability generally show resistance to 5-FU treatment. The present investigation is focussed on the mechanistic insight of a pure herbal carbazole alkaloid, mahanine, as a single or in combination with 5-FU in colon cancer. We demonstrated that mahanine-induced apoptosis involved reactive oxygen species (ROS)-mediated nuclear accumulation of PTEN and its interaction with p53/p73. Mahanine and 5-FU in combination exerted synergistic inhibitory effect on cell viability. This combination also enhanced ROS production, increased tumour suppressor proteins and suppressed chemo-migration. Taken together, our results revealed that mahanine can be a potential chemotherapeutic agent with efficacy to reduce the concentration of toxic 5-FU in colon cancer.
Cancer Biology and Inflammatory Disorder Division, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Kolkata, 700032, India.
Ranjita
R
Das
Kaushik
K
Bhattacharya
Sayantani
S
Sarkar
Suman Kumar
SK
Samanta
Bikas C
BC
Pal
Chitra
C
Mandal
D000970:Antineoplastic Agents / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004338:Drug Combinations; D004357:Drug Synergism; D005472:Fluorouracil / Q000633:toxicity*; D006801:Humans; D032101:Murraya / Q000737:chemistry; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010936:Plant Extracts / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D027821:Rutaceae / Q000737:chemistry; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D002227:Carbazoles; D004268:DNA-Binding Proteins; D004338:Drug Combinations; D009687:Nuclear Proteins; D010936:Plant Extracts; D017382:Reactive Oxygen Species; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C465290:mahanine; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D005472:Fluorouracil