OBJECTIVE 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 investiga...OBJECTIVE 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,apolyisoprenylated benzophenone can chemosensitize HNSCC to cisplatin.METHODS The effect of garcinol and cisplatin on HNSCC was assessed by MTT,Western blotting,real time PCR,FACS,immunohistochemistry,DNA binding assay and xenograft mouse model.RESULTS 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-1,ip 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 ip administration of garcinol at 0.5and 2mg·kg-1 with mean peak concentration(cmax)of 1825.4 and 6635.7nmol·L-1 in the mouse serum,respectively.CONCLUSION Overall,our results suggest that garcinol can indeed potentiate the effects of cisplatin by negative regulation of various inflammatory and proliferative biomarkers.展开更多
In addition to their canonical roles in regulating cell cycle transition and transcription,cyclin-dependent kinases(CDKs)have been shown to coordinate DNA damage response pathways,suggesting a rational pairing of CDK ...In addition to their canonical roles in regulating cell cycle transition and transcription,cyclin-dependent kinases(CDKs)have been shown to coordinate DNA damage response pathways,suggesting a rational pairing of CDK inhibitors with genotoxic chemotherapeutic agents in the treatment of human malignancies.Here,we report that roniciclib(BAY1000394),a potent pan-CDK inhibitor,displays promising anti-neoplastic activity as a single agent and potentiates cisplatin lethality in preclinical nasopharyngeal carcinoma(NPC)models.Proliferation of the NPC cell lines HONE-1,CNE-2,C666-1,and HK-1 was effectively curbed by roniciclib treatment,with IC_(50)values between 11 and 38 nmol/L.These anticancer effects were mediated by pleiotropic mechanisms consistent with successful blockade of cell cycle CDKs 1,2,3,and 4 and transcriptional CDKs 7 and 9,ultimately resulting in arrest at G1/S and G2/M,downregulation of the transcriptional apparatus,and repression of anti-apoptotic proteins.Considerably enhanced tumor cell apoptosis was achieved following combined treatment with 10 nmol/L roniciclib and 2.0μmol/L cisplatin;this combination therapy achieved a response over 250%greater than either drug alone.Although roniciclib chemosensitized NPC cells to cisplatin,it did not sensitize untransformed(NP69)cells.The administration of 0.5 mg/kg roniciclib to BALB/c xenograft mice was well tolerated and effectively restrained tumor growth comparable to treatment with 6 mg/kg cisplatin,whereas combining these two agents produced far greater tumor suppression than either of the monotherapies.In summary,these data demonstrate that roniciclib has strong anti-NPC activity and synergizes with cisplatin chemotherapy at clinically relevant doses,thus justifying further evaluation of this combinatorial approach in clinical settings.展开更多
基金The project supported by National Medical Research Council of Singapore and NUS Academic Research fund
文摘OBJECTIVE 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,apolyisoprenylated benzophenone can chemosensitize HNSCC to cisplatin.METHODS The effect of garcinol and cisplatin on HNSCC was assessed by MTT,Western blotting,real time PCR,FACS,immunohistochemistry,DNA binding assay and xenograft mouse model.RESULTS 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-1,ip 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 ip administration of garcinol at 0.5and 2mg·kg-1 with mean peak concentration(cmax)of 1825.4 and 6635.7nmol·L-1 in the mouse serum,respectively.CONCLUSION Overall,our results suggest that garcinol can indeed potentiate the effects of cisplatin by negative regulation of various inflammatory and proliferative biomarkers.
基金This work was supported by grants from the Singapore Ministry of Health’s National Medical Research Council(NMRC/CSA/021/2010 to B.C.Goh)the National Research Foundation Singapore and Singapore Ministry of Education under their Research Centres of Excellence(RCE)Initiative.
文摘In addition to their canonical roles in regulating cell cycle transition and transcription,cyclin-dependent kinases(CDKs)have been shown to coordinate DNA damage response pathways,suggesting a rational pairing of CDK inhibitors with genotoxic chemotherapeutic agents in the treatment of human malignancies.Here,we report that roniciclib(BAY1000394),a potent pan-CDK inhibitor,displays promising anti-neoplastic activity as a single agent and potentiates cisplatin lethality in preclinical nasopharyngeal carcinoma(NPC)models.Proliferation of the NPC cell lines HONE-1,CNE-2,C666-1,and HK-1 was effectively curbed by roniciclib treatment,with IC_(50)values between 11 and 38 nmol/L.These anticancer effects were mediated by pleiotropic mechanisms consistent with successful blockade of cell cycle CDKs 1,2,3,and 4 and transcriptional CDKs 7 and 9,ultimately resulting in arrest at G1/S and G2/M,downregulation of the transcriptional apparatus,and repression of anti-apoptotic proteins.Considerably enhanced tumor cell apoptosis was achieved following combined treatment with 10 nmol/L roniciclib and 2.0μmol/L cisplatin;this combination therapy achieved a response over 250%greater than either drug alone.Although roniciclib chemosensitized NPC cells to cisplatin,it did not sensitize untransformed(NP69)cells.The administration of 0.5 mg/kg roniciclib to BALB/c xenograft mice was well tolerated and effectively restrained tumor growth comparable to treatment with 6 mg/kg cisplatin,whereas combining these two agents produced far greater tumor suppression than either of the monotherapies.In summary,these data demonstrate that roniciclib has strong anti-NPC activity and synergizes with cisplatin chemotherapy at clinically relevant doses,thus justifying further evaluation of this combinatorial approach in clinical settings.
