Limits...
Dietary restriction-resistant human tumors harboring the PIK3CA-activating mutation H1047R are sensitive to metformin.

Cufí S, Corominas-Faja B, Lopez-Bonet E, Bonavia R, Pernas S, López IÁ, Dorca J, Martínez S, López NB, Fernández SD, Cuyàs E, Visa J, Rodríguez-Gallego E, Quirantes-Piné R, Segura-Carretero A, Joven J, Martin-Castillo B, Menendez JA - Oncotarget (2013)

Bottom Line: The anti-diabetic drug metformin is a stereotypical DR mimetic that exerts its anti-cancer activity through a dual mechanism involving insulin-related (systemic) and mTOR-related (cell-autonomous) effects.Metformin treatment via the i.p. route significantly reduced the proliferation factor mitotic activity index (MAI) and decreased tumor cellularity in MCF10DCIS.com cancer tissues.Whereas SW48-wild-type (PIK3CA+/+) cells rapidly formed metformin-refractory xenotumors in mice, ad libitum access to water containing metformin significantly reduced the growth of SW48-mutated (PIK3CAH1047R/+) xenotumors by approximately 50%.

View Article: PubMed Central - PubMed

Affiliation: Metabolism and Cancer Group, Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia, Spain.

ABSTRACT
Cancer cells expressing constitutively active phosphatidylinositol-3 kinase (PI3K) are proliferative regardless of the absence of insulin, and they form dietary restriction (DR)-resistant tumors in vivo. Because the binding of insulin to its receptors activates the PI3K/AKT/mammalian target of rapamycin (mTOR) signaling cascade, activating mutations in the PIK3CA oncogene may determine tumor response to DR-like pharmacological strategies targeting the insulin and mTOR pathways. The anti-diabetic drug metformin is a stereotypical DR mimetic that exerts its anti-cancer activity through a dual mechanism involving insulin-related (systemic) and mTOR-related (cell-autonomous) effects. However, it remains unclear whether PIK3CA-activating mutations might preclude the anti-cancer activity of metformin in vivo. To model the oncogenic PIK3CA-driven early stages of cancer, we used the clonal breast cancer cell line MCF10DCIS.com, which harbors the gain-of-function H1047R hot-spot mutation in the catalytic domain of the PI3KCA gene and has been shown to form DR-refractory xenotumors. To model PIK3CA-activating mutations in late stages of cancer, we took advantage of the isogenic conversion of a PIK3CA-wild-type tumor into a PIK3CA H1047R-mutated tumor using the highly metastatic colorectal cancer cell line SW48. MCF10DCIS.com xenotumors, although only modestly affected by treatment with oral metformin (approximately 40% tumor growth inhibition), were highly sensitive to the intraperitoneal (i.p.) administration of metformin, the anti-cancer activity of which increased in a time-dependent manner and reached >80% tumor growth inhibition by the end of the treatment. Metformin treatment via the i.p. route significantly reduced the proliferation factor mitotic activity index (MAI) and decreased tumor cellularity in MCF10DCIS.com cancer tissues. Whereas SW48-wild-type (PIK3CA+/+) cells rapidly formed metformin-refractory xenotumors in mice, ad libitum access to water containing metformin significantly reduced the growth of SW48-mutated (PIK3CAH1047R/+) xenotumors by approximately 50%. Thus, metformin can no longer be considered as a bona fide DR mimetic, at least in terms of anti-cancer activity, because tumors harboring the insulin-unresponsive, DR-resistant, PIK3CA-activating mutation H1047R remain sensitive to the anti-tumoral effects of the drug. Given the high prevalence of PIK3CA mutations in human carcinomas and the emerging role of PIK3CA mutation status in the treatment selection process, these findings might have a significant impact on the design of future trials evaluating the potential of combining metformin with targeted therapy.

Show MeSH

Related in: MedlinePlus

Efficacy of oral and i.pmetformin in the DR-resistant MCF10DCIS.com xenograft model. A. Shown are the mean tumor volumes (±SD) of MCF10DCIS.com xenograft-bearing nude mice following oral (ad libitum access to water containing 250 mg kg−1 metformin) and i.p. (daily i.p. injections of 200 mg kg−1 metformin) administration of metformin for 8 weeks. Tumor growth rates were significantly different between the control and the i.p. metformin groups (* Student's t-test P<0.01). B. The bar graph (mean ± SD) shows the quantification of the mitotic activity in the xenografts. The number of mitosis per high power field was quantified by light microscopy in at least ten high power fields per tumor in all xenografts (n=2 per group, three groups; * Student's t-test P<0.01 versus control group). C. Metformin-treated MCF10DCIS.com xenotumors have reduced tumor growth and altered histological features. a-c. Sections from xenografts were stained with H&E and taken at low magnification. a'-c'. Histopathological comparison among MCF10DCIS.com xenografts (evaluation was performed under 400X objective magnification)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3824528&req=5

Figure 1: Efficacy of oral and i.pmetformin in the DR-resistant MCF10DCIS.com xenograft model. A. Shown are the mean tumor volumes (±SD) of MCF10DCIS.com xenograft-bearing nude mice following oral (ad libitum access to water containing 250 mg kg−1 metformin) and i.p. (daily i.p. injections of 200 mg kg−1 metformin) administration of metformin for 8 weeks. Tumor growth rates were significantly different between the control and the i.p. metformin groups (* Student's t-test P<0.01). B. The bar graph (mean ± SD) shows the quantification of the mitotic activity in the xenografts. The number of mitosis per high power field was quantified by light microscopy in at least ten high power fields per tumor in all xenografts (n=2 per group, three groups; * Student's t-test P<0.01 versus control group). C. Metformin-treated MCF10DCIS.com xenotumors have reduced tumor growth and altered histological features. a-c. Sections from xenografts were stained with H&E and taken at low magnification. a'-c'. Histopathological comparison among MCF10DCIS.com xenografts (evaluation was performed under 400X objective magnification)

Mentions: Efficacy of oral metformin in the DR-resistant MCF10DCIS.com xenograft model. Fig. 1A shows the rate of tumor growth in the three treatment groups, with the data plotted as the mean tumor volume in each group over time. Compared with the animals in the vehicle-treated group (mean xenografted MCF10DCIS.com tumor volume of 1794±273 mm3), the animals that received 8 weeks of treatment with oral metformin exhibited slightly decelerated tumor growth, with a final mean tumor volume of 1186±293 mm3 (Fig. 1A). However, none of the differences between the untreated controls and the oral metformin-treated xenotumors over time reached statistical significance. This finding was better reflected by the percent MCF10DCIS.com tumor growth inhibition, which was calculated as follows: 1-treated/control volume ratio (1-T/C). The inhibitory effect of oral metformin was modest, reaching a maximum of 43% at 4 weeks after cell inoculation and decreasing toward the end of the treatment (approximately 30-35%).


Dietary restriction-resistant human tumors harboring the PIK3CA-activating mutation H1047R are sensitive to metformin.

Cufí S, Corominas-Faja B, Lopez-Bonet E, Bonavia R, Pernas S, López IÁ, Dorca J, Martínez S, López NB, Fernández SD, Cuyàs E, Visa J, Rodríguez-Gallego E, Quirantes-Piné R, Segura-Carretero A, Joven J, Martin-Castillo B, Menendez JA - Oncotarget (2013)

Efficacy of oral and i.pmetformin in the DR-resistant MCF10DCIS.com xenograft model. A. Shown are the mean tumor volumes (±SD) of MCF10DCIS.com xenograft-bearing nude mice following oral (ad libitum access to water containing 250 mg kg−1 metformin) and i.p. (daily i.p. injections of 200 mg kg−1 metformin) administration of metformin for 8 weeks. Tumor growth rates were significantly different between the control and the i.p. metformin groups (* Student's t-test P<0.01). B. The bar graph (mean ± SD) shows the quantification of the mitotic activity in the xenografts. The number of mitosis per high power field was quantified by light microscopy in at least ten high power fields per tumor in all xenografts (n=2 per group, three groups; * Student's t-test P<0.01 versus control group). C. Metformin-treated MCF10DCIS.com xenotumors have reduced tumor growth and altered histological features. a-c. Sections from xenografts were stained with H&E and taken at low magnification. a'-c'. Histopathological comparison among MCF10DCIS.com xenografts (evaluation was performed under 400X objective magnification)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824528&req=5

Figure 1: Efficacy of oral and i.pmetformin in the DR-resistant MCF10DCIS.com xenograft model. A. Shown are the mean tumor volumes (±SD) of MCF10DCIS.com xenograft-bearing nude mice following oral (ad libitum access to water containing 250 mg kg−1 metformin) and i.p. (daily i.p. injections of 200 mg kg−1 metformin) administration of metformin for 8 weeks. Tumor growth rates were significantly different between the control and the i.p. metformin groups (* Student's t-test P<0.01). B. The bar graph (mean ± SD) shows the quantification of the mitotic activity in the xenografts. The number of mitosis per high power field was quantified by light microscopy in at least ten high power fields per tumor in all xenografts (n=2 per group, three groups; * Student's t-test P<0.01 versus control group). C. Metformin-treated MCF10DCIS.com xenotumors have reduced tumor growth and altered histological features. a-c. Sections from xenografts were stained with H&E and taken at low magnification. a'-c'. Histopathological comparison among MCF10DCIS.com xenografts (evaluation was performed under 400X objective magnification)
Mentions: Efficacy of oral metformin in the DR-resistant MCF10DCIS.com xenograft model. Fig. 1A shows the rate of tumor growth in the three treatment groups, with the data plotted as the mean tumor volume in each group over time. Compared with the animals in the vehicle-treated group (mean xenografted MCF10DCIS.com tumor volume of 1794±273 mm3), the animals that received 8 weeks of treatment with oral metformin exhibited slightly decelerated tumor growth, with a final mean tumor volume of 1186±293 mm3 (Fig. 1A). However, none of the differences between the untreated controls and the oral metformin-treated xenotumors over time reached statistical significance. This finding was better reflected by the percent MCF10DCIS.com tumor growth inhibition, which was calculated as follows: 1-treated/control volume ratio (1-T/C). The inhibitory effect of oral metformin was modest, reaching a maximum of 43% at 4 weeks after cell inoculation and decreasing toward the end of the treatment (approximately 30-35%).

Bottom Line: The anti-diabetic drug metformin is a stereotypical DR mimetic that exerts its anti-cancer activity through a dual mechanism involving insulin-related (systemic) and mTOR-related (cell-autonomous) effects.Metformin treatment via the i.p. route significantly reduced the proliferation factor mitotic activity index (MAI) and decreased tumor cellularity in MCF10DCIS.com cancer tissues.Whereas SW48-wild-type (PIK3CA+/+) cells rapidly formed metformin-refractory xenotumors in mice, ad libitum access to water containing metformin significantly reduced the growth of SW48-mutated (PIK3CAH1047R/+) xenotumors by approximately 50%.

View Article: PubMed Central - PubMed

Affiliation: Metabolism and Cancer Group, Translational Research Laboratory, Catalan Institute of Oncology, Girona, Catalonia, Spain.

ABSTRACT
Cancer cells expressing constitutively active phosphatidylinositol-3 kinase (PI3K) are proliferative regardless of the absence of insulin, and they form dietary restriction (DR)-resistant tumors in vivo. Because the binding of insulin to its receptors activates the PI3K/AKT/mammalian target of rapamycin (mTOR) signaling cascade, activating mutations in the PIK3CA oncogene may determine tumor response to DR-like pharmacological strategies targeting the insulin and mTOR pathways. The anti-diabetic drug metformin is a stereotypical DR mimetic that exerts its anti-cancer activity through a dual mechanism involving insulin-related (systemic) and mTOR-related (cell-autonomous) effects. However, it remains unclear whether PIK3CA-activating mutations might preclude the anti-cancer activity of metformin in vivo. To model the oncogenic PIK3CA-driven early stages of cancer, we used the clonal breast cancer cell line MCF10DCIS.com, which harbors the gain-of-function H1047R hot-spot mutation in the catalytic domain of the PI3KCA gene and has been shown to form DR-refractory xenotumors. To model PIK3CA-activating mutations in late stages of cancer, we took advantage of the isogenic conversion of a PIK3CA-wild-type tumor into a PIK3CA H1047R-mutated tumor using the highly metastatic colorectal cancer cell line SW48. MCF10DCIS.com xenotumors, although only modestly affected by treatment with oral metformin (approximately 40% tumor growth inhibition), were highly sensitive to the intraperitoneal (i.p.) administration of metformin, the anti-cancer activity of which increased in a time-dependent manner and reached >80% tumor growth inhibition by the end of the treatment. Metformin treatment via the i.p. route significantly reduced the proliferation factor mitotic activity index (MAI) and decreased tumor cellularity in MCF10DCIS.com cancer tissues. Whereas SW48-wild-type (PIK3CA+/+) cells rapidly formed metformin-refractory xenotumors in mice, ad libitum access to water containing metformin significantly reduced the growth of SW48-mutated (PIK3CAH1047R/+) xenotumors by approximately 50%. Thus, metformin can no longer be considered as a bona fide DR mimetic, at least in terms of anti-cancer activity, because tumors harboring the insulin-unresponsive, DR-resistant, PIK3CA-activating mutation H1047R remain sensitive to the anti-tumoral effects of the drug. Given the high prevalence of PIK3CA mutations in human carcinomas and the emerging role of PIK3CA mutation status in the treatment selection process, these findings might have a significant impact on the design of future trials evaluating the potential of combining metformin with targeted therapy.

Show MeSH
Related in: MedlinePlus