Combined inhibition of Dnmt and mTOR signaling inhibits formation and growth of colorectal cancer.
OBJECTIVE
Although the anticancer effects of rapamycin (RPM) and 5-aza-deoxycytidine (AZA) have been studied extensively, the combined effect of these two drugs on colorectal cancer (CRC) is still unknown. This study addresses the effect of AZA and RPM combination therapy on CRC and its influence on the mammalian target of rapamycin (mTOR) and its signal transduction pathway.


METHODS
Human CRC cell line HCT116 was treated with AZA alone, RPM alone, or concurrently with a combination of both drugs. Cell viability, apoptosis, and cell cycle distribution were analyzed. CRC was initiated in S-ICR mice, which were then treated with the drugs mentioned above, and tumor incidence and volume were measured. The activity of the mTOR signal transduction pathway was detected by Western blot analysis or immunohistochemistry.


RESULTS
Combination treatment with AZA and RPM inhibited the growth of HCT116 cells, induced apoptosis, arrested the cell cycle, and reduced the incidence and tumor volume of CRC in mice, as well as inhibited the phosphorylation of components of the mTOR signal transduction pathway. These effects were more significant than those of single-drug treatments.


CONCLUSIONS
Combination treatment with AZA and RPM inhibits the formation and growth of CRC. These findings may provide a novel strategy for CRC treatment.
Zhang
Yan-Jie
YJ
Shanghai Institute of Digestive Disease, Shanghai Jiaotong University School of Medicine Renji Hospital, 145 Shandong Road Middle, Shanghai, 200001, China.
Zhao
Shu-Liang
SL
Tian
Xiao-Qing
XQ
Sun
Dan-Feng
DF
Xiong
Hua
H
Dai
Qiang
Q
Li
Xiao-Qiang
XQ
Fang
Jing-Yuan
JY
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000473:pathology*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors*; D004357:Drug Synergism; D045325:HCT116 Cells; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D047368:Tumor Burden / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D004248:DNA (Cytosine-5-)-Methyltransferases; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D001374:Azacitidine; D020123:Sirolimus