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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.

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In vivo growth-inhibitory effect of co-treatment of ZOL with TMZ on MGMT-expressing malignant glioma xenografts.A, Anti-tumor effect of TMZ and ZOL combination in human malignant glioma LN-18 cell line. BALB/cA nude mice (female, 5–6 weeks old) bearing LN-18 tumor were separated into four treatment groups; None, TMZ, ZOL and TMZ + ZOL. TMZ (10 mg/kg) was administered i.p. on day 1, 2, 3, 4, 5. ZOL (5 mg/kg) was injected i.p. on day 1, 3, 5 of each week for 2 weeks. At day 35, combination of TMZ and ZOL apparently inhibited tumor growth of LN-18. B, Anti-tumor effect of TMZ and ZOL combination in human malignant glioma LN-18 cell line.Left BALB/cA nude mice bearing LN-18 tumor were treated with or without TMZ and/or ZOL. Tumor length and width were measured in situ with digital calipers once a week for 5 weeks (35 days). Tumor volume was calculated once a week for 5 weeks (35 days) according to the following equation: tumor volume (mm3)  = π/6×length× (width)2. Points represent mean values ± SE. Combination of TMZ and ZOL significantly inhibited tumor growth of LN-18. Right In the same experiment as Left, body weight was measured once a week for 5 weeks (35 days). Points represent mean values ± SE. Approximate 10% body weight loss occurred in treated mice, whereas body weight was recovered during the observation period.
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pone-0104538-g006: In vivo growth-inhibitory effect of co-treatment of ZOL with TMZ on MGMT-expressing malignant glioma xenografts.A, Anti-tumor effect of TMZ and ZOL combination in human malignant glioma LN-18 cell line. BALB/cA nude mice (female, 5–6 weeks old) bearing LN-18 tumor were separated into four treatment groups; None, TMZ, ZOL and TMZ + ZOL. TMZ (10 mg/kg) was administered i.p. on day 1, 2, 3, 4, 5. ZOL (5 mg/kg) was injected i.p. on day 1, 3, 5 of each week for 2 weeks. At day 35, combination of TMZ and ZOL apparently inhibited tumor growth of LN-18. B, Anti-tumor effect of TMZ and ZOL combination in human malignant glioma LN-18 cell line.Left BALB/cA nude mice bearing LN-18 tumor were treated with or without TMZ and/or ZOL. Tumor length and width were measured in situ with digital calipers once a week for 5 weeks (35 days). Tumor volume was calculated once a week for 5 weeks (35 days) according to the following equation: tumor volume (mm3)  = π/6×length× (width)2. Points represent mean values ± SE. Combination of TMZ and ZOL significantly inhibited tumor growth of LN-18. Right In the same experiment as Left, body weight was measured once a week for 5 weeks (35 days). Points represent mean values ± SE. Approximate 10% body weight loss occurred in treated mice, whereas body weight was recovered during the observation period.

Mentions: We also investigated the effect of TMZ and ZOL combination on subcutaneous LN-18 xenografts. Tumors were allowed to grow until around 500 mm3, and then treatments were initiated. As shown in Fig. 6A and B, either TMZ (10 mg/kg) or ZOL (5 mg/kg) decreased the tumor growth to a mild extent, whereas a combination of TMZ and ZOL substantially enhanced the suppression of the tumor growth. Although approximate 10% body weight loss occurred in treated mice, body weight was recovered during the observation period (Fig. 6B). These results clearly show the significant in vivo activity of the combination treatment against the LN-18 tumor xenograft.


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)

In vivo growth-inhibitory effect of co-treatment of ZOL with TMZ on MGMT-expressing malignant glioma xenografts.A, Anti-tumor effect of TMZ and ZOL combination in human malignant glioma LN-18 cell line. BALB/cA nude mice (female, 5–6 weeks old) bearing LN-18 tumor were separated into four treatment groups; None, TMZ, ZOL and TMZ + ZOL. TMZ (10 mg/kg) was administered i.p. on day 1, 2, 3, 4, 5. ZOL (5 mg/kg) was injected i.p. on day 1, 3, 5 of each week for 2 weeks. At day 35, combination of TMZ and ZOL apparently inhibited tumor growth of LN-18. B, Anti-tumor effect of TMZ and ZOL combination in human malignant glioma LN-18 cell line.Left BALB/cA nude mice bearing LN-18 tumor were treated with or without TMZ and/or ZOL. Tumor length and width were measured in situ with digital calipers once a week for 5 weeks (35 days). Tumor volume was calculated once a week for 5 weeks (35 days) according to the following equation: tumor volume (mm3)  = π/6×length× (width)2. Points represent mean values ± SE. Combination of TMZ and ZOL significantly inhibited tumor growth of LN-18. Right In the same experiment as Left, body weight was measured once a week for 5 weeks (35 days). Points represent mean values ± SE. Approximate 10% body weight loss occurred in treated mice, whereas body weight was recovered during the observation period.
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Related In: Results  -  Collection

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

pone-0104538-g006: In vivo growth-inhibitory effect of co-treatment of ZOL with TMZ on MGMT-expressing malignant glioma xenografts.A, Anti-tumor effect of TMZ and ZOL combination in human malignant glioma LN-18 cell line. BALB/cA nude mice (female, 5–6 weeks old) bearing LN-18 tumor were separated into four treatment groups; None, TMZ, ZOL and TMZ + ZOL. TMZ (10 mg/kg) was administered i.p. on day 1, 2, 3, 4, 5. ZOL (5 mg/kg) was injected i.p. on day 1, 3, 5 of each week for 2 weeks. At day 35, combination of TMZ and ZOL apparently inhibited tumor growth of LN-18. B, Anti-tumor effect of TMZ and ZOL combination in human malignant glioma LN-18 cell line.Left BALB/cA nude mice bearing LN-18 tumor were treated with or without TMZ and/or ZOL. Tumor length and width were measured in situ with digital calipers once a week for 5 weeks (35 days). Tumor volume was calculated once a week for 5 weeks (35 days) according to the following equation: tumor volume (mm3)  = π/6×length× (width)2. Points represent mean values ± SE. Combination of TMZ and ZOL significantly inhibited tumor growth of LN-18. Right In the same experiment as Left, body weight was measured once a week for 5 weeks (35 days). Points represent mean values ± SE. Approximate 10% body weight loss occurred in treated mice, whereas body weight was recovered during the observation period.
Mentions: We also investigated the effect of TMZ and ZOL combination on subcutaneous LN-18 xenografts. Tumors were allowed to grow until around 500 mm3, and then treatments were initiated. As shown in Fig. 6A and B, either TMZ (10 mg/kg) or ZOL (5 mg/kg) decreased the tumor growth to a mild extent, whereas a combination of TMZ and ZOL substantially enhanced the suppression of the tumor growth. Although approximate 10% body weight loss occurred in treated mice, body weight was recovered during the observation period (Fig. 6B). These results clearly show the significant in vivo activity of the combination treatment against the LN-18 tumor xenograft.

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