Obovatol Enhances Docetaxel-Induced Prostate and Colon Cancer Cell Death Through Inactivation of Nuclear Transcription Factor-κB

Abstract

Abstract. Nuclear transcription factor-κB (NF-κB) 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-κB activity. We investigated here whether obovatol could sensitize cancer cells against docetaxel through inhibition of NF-κB 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 μM 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-κB activities as well as expression of NF-κB 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-κB activity were also found. These results indicate that obovatol augments cell growth inhibition by chemotherapeutics through inactivation of NF-κB and suggest that obovatol may have therapeutic advantages in the combination treatment with other chemotherapeutics. [Supplementary Figure: available only at http://dx

Cisplatin Resistance: A Cellular Self-Defense Mechanism Resulting from Multiple Epigenetic and Genetic Changes

“…These factors include the Y-box binding protein-1, CCAAT-binding transcription factor 2, activating transcription factor 4, zincfinger factor 143, the nuclear transcription factor-B, the microphthalmia-associated transcription factor, the forkhead transcription factor O, and mitochondrial transcription factor A (Torigoe et al, 2005;Lee et al, 2009;Lei and Quelle, 2009;Li et al, 2009;Keenen et al, 2010). Hirano et al (2010) reported that p300/CBP-associated factor (PCAF) was overexpressed in human prostate and epidermal cisplatin-resistant P/CDP6 and HeLa/CP4 cells.…”

HJC, a New Arylnaphthalene Lignan Isolated From Justicia procumbens, Causes Apoptosis and Caspase Activation in K562 Leukemia Cells

“…Deoxypodophyllotoxin and podophyllotoxin (POD) are two well-known naturally occurring aryltetralin lignans. Both compounds are cytotoxic (1), and their derivatives such as etoposide (ETO) (2,3), teniposide (4), and etopophos have potential clinical use as antitumor agents (5,6). However, due to the drug resistance developed by cancer cells as well as side effects associated with the use of these agents in the clinic (including myelosuppression, neutropenia, and nausea), the search for new effective anticancer analogs remains an intense area of research (7,8).…”

Magnetic nanoparticles of Fe3O4 enhance docetaxel-induced prostate cancer cell death

“…However, to be effective, DTX must be administered at such high doses that can induce significant toxicity. 9,17 To overcome this drawback, combination therapies have been developed; DTX combined with tyrosine kinase or bcl-2 inhibitors are currently in Phase II studies for treating CRPC. 17 Drug-delivery assemblies consisting of a nanocarrier, a targeting agent, and DTX have also been developed.…”

“…Moreover, the current regimen requires the administration of high doses of DTX, which causes toxic reactions and thereby precludes the use of DTX as a monotherapy. 9 To reduce toxicity and to improve the survival and quality of life of CRPC patients, novel therapeutic strategies targeting the molecular basis of androgen-and chemo-resistance of prostate cancer using a reduced but equieffective dose of DTX should be developed.…”