Garcinol sensitizes human head and neck carcinoma to cisplatin in a xenograft mouse model despite downregulation of proliferative biomarkers

Abstract

Platinum compounds such as cisplatin and carboplatin are frequently used as the first-line chemotherapy for the treatment of the head and neck squamous cell carcinoma (HNSCC). In the present study, we investigated whether garcinol, a polyisoprenylated benzophenone can chemosensitize HNSCC to cisplatin. We found that garcinol inhibited the viability of a panel of diverse HNSCC cell lines, enhanced the apoptotic effect of cisplatin, suppressed constitutive as well as cisplatin-induced NF-κB activation, and downregulated the expression of various oncogenic gene products (cyclin D1, Bcl-2, survivin and VEGF). In vivo study showed that administration of garcinol alone (0.5 mg/kg body weight, i.p. five times/week) significantly suppressed the growth of the tumor, and this effect was further increased by cisplatin. Both the markers of proliferation index (Ki-67) and microvessel density (CD31) were downregulated in tumor tissues by the combination of cisplatin and garcinol. The pharmacokinetic results of garcinol indicated that good systemic exposure was achievable after i.p. administration of garcinol at 0.5 mg/kg and 2 mg/kg with mean peak concentration (Cmax) of 1825.4 and 6635.7 nM in the mouse serum, respectively. Overall, our results suggest that garcinol can indeed potentiate the effects of cisplatin by negative regulation of various inflammatory and proliferative biomarkers.

A chemogenomic screening identifies CK2 as a target for pro-senescence therapy in PTEN-deficient tumours

“…Twelve out of 33 compounds had a marked difference in the IC50 between Pten fl/fl and Pten À / À cells (Pten À / À IC50 r 60% Pten fl/flIC50 ) and were selected for the final step of the screening. Examples of compounds that did not pass the optimization filter despite a previous selectivity at single dosage were: Clotrimazole 8,9 , Clomipramine hydrochloride 10 , Nifedipine 11 , Trichostatin A 12,13 and Garcinol 14 (not specific cell growth arrest between Pten fl/fl and Pten À / À cells at the IC50). Finally, compounds were tested in SA-b-gal assay using both the cell lines to test for cellular senescence induction (SA-b-gal filter).…”

Natural compound Oblongifolin C confers gemcitabine resistance in pancreatic cancer by downregulating Src/MAPK/ERK pathways

“…Li F et al . showed that Garcinol, a natural polyisoprenylated benzophenone derivative (PPAP), chemosensitized head and neck squamous cell carcinoma b negatively regulating constitutive cisplatin-induced nuclear factor-kB activation and the expression of oncogenic gene product 22 .…”

Evidence for the Involvement of the Master Transcription Factor NF-κB in Cancer Initiation and Progression

“…Several chemotherapeutic agents, including paclitaxel, vinblastine, vincristine, doxorubicin, and daunomycin have been reported to induce NF-κB activation in different cells However, it has also been found that the nature of the genes expressed following chemotherapy-induced NF-κB activation is context dependent and this activation can result in both the expression or suppression of anti-apoptotic genes [ 34 , 35 , 36 , 37 ].…”