Hexamethylene bisacetamide (HMBA) simultaneously targets AKT and MAPK pathway and represses NF kappaB activity: implications for cancer therapy.
Hexamethylene Bisacetamide (HMBA) is a hybrid polar compound originally developed as a differentiation inducing agent. We show in this study that HMBA can inhibit activation of several NF kappaB target genes in both lung and breast cancer cell lines. Furthermore, consistent with its ability to inhibit NF kappaB function, HMBA can also sensitize cells to apoptosis. We show that HMBA mediates inhibition of the Akt and ERK/MAPK cascade, both of which are critical for cell survival and proliferation and are well known regulators of NF kappaB activation. We also show that PTEN negative breast cancer cells which have hyper activation of the PI3K/Akt pathway show increased sensitivity to growth inhibitory effects of combination of HMBA and TNFalpha. Furthermore, HMBA can decrease the kinase activity of the IKK complex leading to defective phosphorylation of I kappaB alpha and Ser536 of p65. This study gives mechanistic insight into the mechanism of action of HMBA, provides the rationale for the potential use of HMBA in combination with various existing kinase inhibitors in combination therapy and also suggests useful biomarkers for monitoring tumor response to HMBA.
Dey
Anwesha
A
Laboratory of Cell Cycle Control, Institute of Molecular and Cell Biology, Proteos, Singapore, Singapore.
Wong
Eetsin
E
Kua
Nelly
N
Teo
Hsiang Ling
HL
Tergaonkar
Vinay
V
Lane
David
D
D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051550:I-kappa B Kinase / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051059:PTEN Phosphohydrolase / Q000172:deficiency; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D051996:Transcription Factor RelA / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000081:Acetamides; D016328:NF-kappa B; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; D048049:Extracellular Signal-Regulated MAP Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C014026:hexamethylene bisacetamide