Obovatol enhances docetaxel-induced prostate and colon cancer cell death through inactivation of nuclear transcription factor-kappaB.
Nuclear transcription factor-kappaB (NF-kappaB) is constitutively activated in prostate and colon cancers and is related with the resistance of cancer cells against chemotherapeutics. Previously, we found that obovatol, an active compound isolated from Magnolia obovata, inhibited cancer cell growth through inhibition of NF-kappaB activity. We investigated here whether obovatol could sensitize cancer cells against docetaxel through inhibition of NF-kappaB activity in prostate cancer (LNCaP and PC-3) and colon cancer (SW620 and HCT116) cells. The combination treatment with each drug at one half the respective IC(50) dose (5 microM obovatol + 5 nM docetaxel) was more effective and significant (60%-70%) in the inhibition of cancer cell growth than single treatment by each drug (20%-40%); inhibition was exerted through a significant increase of apoptosis induction (60%-80%) by the combination treatment compared to the single treatment (10%-30%). Correlating well with the synergistic inhibition (combination indices are less than 1 in all cell types), the combination significantly inhibited NF-kappaB activities as well as expression of NF-kappaB target apoptotic cell death proteins, but decreased anti-apoptotic cell death proteins. Similar combination effects of obovatol with other chemotherapeutic agents (paclitaxel, cisplatin, and doxorubicin) on the inhibition of cell growth and NF-kappaB activity were also found. These results indicate that obovatol augments cell growth inhibition by chemotherapeutics through inactivation of NF-kappaB and suggest that obovatol may have therapeutic advantages in the combination treatment with other chemotherapeutics. [Supplementary Figure: available only at http://dx.doi.org/10.1254/jphs.09048FP].
Lee
So Yong
SY
College of Pharmacy and CBITRC, Chungbuk National University, South Korea.
Cho
Jin Suk
JS
Yuk
Dong Yeon
DY
Moon
Dong Cheul
DC
Jung
Jae Kyung
JK
Yoo
Hwan Soo
HS
Lee
Young Moon
YM
Han
Sang Bae
SB
Oh
Ki-Wan
KW
Hong
Jin Tae
JT
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D000077143:Docetaxel; D004357:Drug Synergism; D005456:Fluorescent Dyes / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D007211:Indoles / Q000378:metabolism; D020128:Inhibitory Concentration 50; D031566:Magnolia / Q000737:chemistry; D008297:Male; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010647:Phenyl Ethers / Q000737:chemistry / Q000494:pharmacology; D018515:Plant Leaves / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D001713:Biphenyl Compounds; D005456:Fluorescent Dyes; D007211:Indoles; D016328:NF-kappa B; D010647:Phenyl Ethers; D043823:Taxoids; D000077143:Docetaxel; C007293:DAPI; C036795:obovatol