Limits...
Enhanced anti-tumor effect of zoledronic acid combined with temozolomide against human malignant glioma cell expressing O6-methylguanine DNA methyltransferase.

Fukai J, Koizumi F, Nakao N - PLoS ONE (2014)

Bottom Line: However, combination experiment of TMZ plus ZOL revealed that a supra-additive effect resulted in a significant decrease in cell growth.In combined TMZ/ZOL treatment, an increased apoptotic rate was apparent and significant activation of caspase-3 and cleavage of poly-(ADP-ribose) polymerase were observed compared with each single drug exposure.Subcutanous xenograft models showed significant decrease of tumor growth with combined TMZ/ZOL treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurological Surgery, Wakayama Medical University School of Medicine, Wakayama, Japan; Shien-Lab, National Cancer Center Hospital, Tokyo, Japan.

ABSTRACT
Temozolomide (TMZ), a DNA methylating agent, is widely used in the adjuvant treatment of malignant gliomas. O6-methylguanine-DNA methyltranferase (MGMT), a DNA repair enzyme, is frequently discussed as the main factor that limits the efficacy of TMZ. Zoledronic acid (ZOL), which is clinically applied to treat cancer-induced bone diseases, appears to possess direct anti-tumor activity through apoptosis induction by inhibiting mevalonate pathway and prenylation of intracellular small G proteins. In this study, we evaluated whether ZOL can be effectively used as an adjuvant to TMZ in human malignant glioma cells that express MGMT. Malignant glioma cell lines, in which the expression of MGMT was detected, did not exhibit growth inhibition by TMZ even at a longer exposure. However, combination experiment of TMZ plus ZOL revealed that a supra-additive effect resulted in a significant decrease in cell growth. In combined TMZ/ZOL treatment, an increased apoptotic rate was apparent and significant activation of caspase-3 and cleavage of poly-(ADP-ribose) polymerase were observed compared with each single drug exposure. There were decreased amounts of Ras-GTP, MAPK and Akt phosphorylation and MGMT expression in the ZOL-treated cells. Subcutanous xenograft models showed significant decrease of tumor growth with combined TMZ/ZOL treatment. These results suggest that ZOL efficaciously inhibits activity of Ras in malignant glioma cells and potentiates TMZ-mediated cytotoxicity, inducing growth inhibition and apoptosis of malignant glioma cells that express MGMT and resistant to TMZ. Based on this work, combination of TMZ with ZOL might be a potential therapy in malignant gliomas that receive less therapeutic effects of TMZ due to cell resistance.

Show MeSH

Related in: MedlinePlus

A diagram of the proposed mechanism showing anti-tumor effect of TMZ in combination with ZOL against malignant glioma cells expressing MGMT.According to the results of the present study, ZOL inhibits the activity of Ras and the expression of MGMT in malignant glioma cells and potentiates TMZ-mediated cytotoxicity, inducing growth inhibition and apoptosis of malignant glioma cells that express MGMT and resistant to TMZ. The molecular mechanism leading to the pathway indicated by the dotted arrow remains to be determined.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4128678&req=5

pone-0104538-g007: A diagram of the proposed mechanism showing anti-tumor effect of TMZ in combination with ZOL against malignant glioma cells expressing MGMT.According to the results of the present study, ZOL inhibits the activity of Ras and the expression of MGMT in malignant glioma cells and potentiates TMZ-mediated cytotoxicity, inducing growth inhibition and apoptosis of malignant glioma cells that express MGMT and resistant to TMZ. The molecular mechanism leading to the pathway indicated by the dotted arrow remains to be determined.

Mentions: Although TMZ chemotherapy is a standard of adjuvant treatment against glioblastomas, there remains to be an important problem how to control glioblastomas refractory to this therapy. Also, in our experiments, malignant glioma cells expressing MGMT were less sensitive to TMZ, as reported elsewhere [9], [10], [11]. To efficiently suppress TMZ-resistant tumors, additional therapeutic strategies are necessary and drug combination will enable the potential development of new adjuvant treatments. The present data provide evidence that ZOL efficaciously inhibits the activity of Ras and the expression of MGMT in malignant glioma cells and potentiates TMZ-mediated cytotoxicity, inducing growth inhibition and apoptosis of malignant glioma cells that express MGMT and resistant to TMZ (Fig. 7). These results suggest that combination of ZOL with TMZ therapy might be effective against malignant gliomas refractory to TMZ.


Enhanced anti-tumor effect of zoledronic acid combined with temozolomide against human malignant glioma cell expressing O6-methylguanine DNA methyltransferase.

Fukai J, Koizumi F, Nakao N - PLoS ONE (2014)

A diagram of the proposed mechanism showing anti-tumor effect of TMZ in combination with ZOL against malignant glioma cells expressing MGMT.According to the results of the present study, ZOL inhibits the activity of Ras and the expression of MGMT in malignant glioma cells and potentiates TMZ-mediated cytotoxicity, inducing growth inhibition and apoptosis of malignant glioma cells that express MGMT and resistant to TMZ. The molecular mechanism leading to the pathway indicated by the dotted arrow remains to be determined.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4128678&req=5

pone-0104538-g007: A diagram of the proposed mechanism showing anti-tumor effect of TMZ in combination with ZOL against malignant glioma cells expressing MGMT.According to the results of the present study, ZOL inhibits the activity of Ras and the expression of MGMT in malignant glioma cells and potentiates TMZ-mediated cytotoxicity, inducing growth inhibition and apoptosis of malignant glioma cells that express MGMT and resistant to TMZ. The molecular mechanism leading to the pathway indicated by the dotted arrow remains to be determined.
Mentions: Although TMZ chemotherapy is a standard of adjuvant treatment against glioblastomas, there remains to be an important problem how to control glioblastomas refractory to this therapy. Also, in our experiments, malignant glioma cells expressing MGMT were less sensitive to TMZ, as reported elsewhere [9], [10], [11]. To efficiently suppress TMZ-resistant tumors, additional therapeutic strategies are necessary and drug combination will enable the potential development of new adjuvant treatments. The present data provide evidence that ZOL efficaciously inhibits the activity of Ras and the expression of MGMT in malignant glioma cells and potentiates TMZ-mediated cytotoxicity, inducing growth inhibition and apoptosis of malignant glioma cells that express MGMT and resistant to TMZ (Fig. 7). These results suggest that combination of ZOL with TMZ therapy might be effective against malignant gliomas refractory to TMZ.

Bottom Line: However, combination experiment of TMZ plus ZOL revealed that a supra-additive effect resulted in a significant decrease in cell growth.In combined TMZ/ZOL treatment, an increased apoptotic rate was apparent and significant activation of caspase-3 and cleavage of poly-(ADP-ribose) polymerase were observed compared with each single drug exposure.Subcutanous xenograft models showed significant decrease of tumor growth with combined TMZ/ZOL treatment.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurological Surgery, Wakayama Medical University School of Medicine, Wakayama, Japan; Shien-Lab, National Cancer Center Hospital, Tokyo, Japan.

ABSTRACT
Temozolomide (TMZ), a DNA methylating agent, is widely used in the adjuvant treatment of malignant gliomas. O6-methylguanine-DNA methyltranferase (MGMT), a DNA repair enzyme, is frequently discussed as the main factor that limits the efficacy of TMZ. Zoledronic acid (ZOL), which is clinically applied to treat cancer-induced bone diseases, appears to possess direct anti-tumor activity through apoptosis induction by inhibiting mevalonate pathway and prenylation of intracellular small G proteins. In this study, we evaluated whether ZOL can be effectively used as an adjuvant to TMZ in human malignant glioma cells that express MGMT. Malignant glioma cell lines, in which the expression of MGMT was detected, did not exhibit growth inhibition by TMZ even at a longer exposure. However, combination experiment of TMZ plus ZOL revealed that a supra-additive effect resulted in a significant decrease in cell growth. In combined TMZ/ZOL treatment, an increased apoptotic rate was apparent and significant activation of caspase-3 and cleavage of poly-(ADP-ribose) polymerase were observed compared with each single drug exposure. There were decreased amounts of Ras-GTP, MAPK and Akt phosphorylation and MGMT expression in the ZOL-treated cells. Subcutanous xenograft models showed significant decrease of tumor growth with combined TMZ/ZOL treatment. These results suggest that ZOL efficaciously inhibits activity of Ras in malignant glioma cells and potentiates TMZ-mediated cytotoxicity, inducing growth inhibition and apoptosis of malignant glioma cells that express MGMT and resistant to TMZ. Based on this work, combination of TMZ with ZOL might be a potential therapy in malignant gliomas that receive less therapeutic effects of TMZ due to cell resistance.

Show MeSH
Related in: MedlinePlus