Combined Treatment with Exendin-4 and Metformin Attenuates Prostate Cancer Growth.

Tsutsumi Y, Nomiyama T, Kawanami T, Hamaguchi Y, Terawaki Y, Tanaka T, Murase K, Motonaga R, Tanabe M, Yanase T

PloS one6 Oct 2015Cited by 43 (Europe PMC)

PMID26439622PMCIDPMC4595004DOI10.1371/journal.pone.0139709PepBankPUB-26439622

Summary

IntroductionRecently, the pleiotropic benefits of incretin-based therapy have been reported. We have previously reported that Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, attenuates prostate cancer growth. Metformin is known for its anti-cancer effect. Here, we examined the anti-cancer effect of Exendin-4 and metformin using a prostate cancer model.MethodsProstate cancer cells were treated with Exendin-4 and/or metformin. Cell proliferation was quantified by growth curves and 5-bromo-2'-deoxyuridine (BrdU) assay. TUNEL assay and AMP-activated protein kinase (AMPK) phosphorylation were examined in LNCaP cells. For in vivo experiments, LNCaP cells were transplanted subcutaneously into the flank region of athymic mice, which were then treated with Exendin-4 and/or metformin. TUNEL assay and immunohistochemistry were performed on tumors.ResultsExendin-4 and metformin additively decreased the growth curve, but not the migration, of prostate cancer cells. The BrdU assay revealed that both Exendin-4 and metformin significantly decreased prostate cancer cell proliferation. Furthermore, metformin, but not Exendin-4, activated AMPK and induced apoptosis in LNCaP cells. The anti-proliferative effect of metformin was abolished by inhibition or knock down of AMPK. In vivo, Exendin-4 and metformin significantly decreased tumor size, and further significant tumor size reduction was observed after combined treatment. Immunohistochemistry on tumors revealed that the P504S and Ki67 expression decreased by Exendin-4 and/or metformin, and that metformin increased phospho-AMPK expression and the apoptotic cell number.ConclusionThese data suggest that Exendin-4 and metformin attenuated prostate cancer growth by inhibiting proliferation, and that metformin inhibited proliferation by inducing apoptosis. Combined treatment with Exendin-4 and metformin attenuated prostate cancer growth more than separate treatments.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study12

7 results from studies that gave the peptide. No result from this study comes from people.

01AnimalAnimal study (in vivo)Efficacy outcome
In mice bearing prostate tumors, Exendin‑4 significantly decreased tumor size.
In plain wordsIn mice with prostate tumors, Exendin‑4 reduced tumor size.
Peptide
Exenatide (exendin-4)
Outcome
DecreaseTumor size with Exendin-4 alone
Study
mousen: not reported in source
Athymic mice bearing LNCaP tumors
Outcome group
Tumor growth · Cancer
Studied dose
Dose not stated
Source sentences
Summary
In vivo, Exendin-4 and metformin significantly decreased tumor size, and further significant tumor size reduction was observed after combined treatment.
1 context sentence(design, population, supporting numbers)
Summary · context
For in vivo experiments, LNCaP cells were transplanted subcutaneously into the flank region of athymic mice, which were then treated with Exendin-4 and/or metformin.
Show in the study text Report a problemFND-2643962206
02AnimalAnimal study (in vivo)Efficacy outcome
In mice bearing prostate tumors, adding Exendin‑4 to metformin further reduced tumor size compared with metformin alone.
In plain wordsIn mice with prostate tumors, adding Exendin‑4 to metformin reduced tumor size more than metformin alone.
Peptide
Exenatide (exendin-4)
Outcome
DecreaseCombination tumor size versus metformin
Study
mousen: not reported in source
Athymic mice bearing LNCaP tumors
Comparator
Metformin alone
Outcome group
Tumor growth · Cancer
Studied dose
Dose not stated
Source sentences
Summary
In vivo, Exendin-4 and metformin significantly decreased tumor size, and further significant tumor size reduction was observed after combined treatment.
1 context sentence(design, population, supporting numbers)
Summary · context
For in vivo experiments, LNCaP cells were transplanted subcutaneously into the flank region of athymic mice, which were then treated with Exendin-4 and/or metformin.
Show in the study text Report a problemFND-2643962207
03AnimalAnimal study (in vivo)Mechanism
In mice bearing prostate tumors, Exendin‑4 decreased tumor P504S expression.
In plain wordsIn mice with prostate tumors, Exendin‑4 decreased the tumor marker P504S.
Peptide
Exenatide (exendin-4)
Outcome
DecreaseTumor P504S expression
Study
mousen: not reported in source
Athymic mice bearing LNCaP tumors
Outcome group
Tumor growth · Cancer
Studied dose
Dose not stated
Source sentences
Summary
Immunohistochemistry on tumors revealed that the P504S and Ki67 expression decreased by Exendin-4 and/or metformin,
1 context sentence(design, population, supporting numbers)
Summary · context
For in vivo experiments, LNCaP cells were transplanted subcutaneously into the flank region of athymic mice, which were then treated with Exendin-4 and/or metformin.
Show in the study text Report a problemFND-2643962209
04AnimalAnimal study (in vivo)Mechanism
In mice bearing prostate tumors, Exendin‑4 decreased tumor Ki67 expression.
In plain wordsIn mice with prostate tumors, Exendin‑4 decreased the proliferation marker Ki67.
Peptide
Exenatide (exendin-4)
Outcome
DecreaseTumor Ki67 expression
Study
mousen: not reported in source
Athymic mice bearing LNCaP tumors
Outcome group
Tumor growth · Cancer
Studied dose
Dose not stated
Source sentences
Summary
Immunohistochemistry on tumors revealed that the P504S and Ki67 expression decreased by Exendin-4 and/or metformin,
1 context sentence(design, population, supporting numbers)
Summary · context
For in vivo experiments, LNCaP cells were transplanted subcutaneously into the flank region of athymic mice, which were then treated with Exendin-4 and/or metformin.
Show in the study text Report a problemFND-2643962210
05LabIn vitro (cells)Efficacy outcome
In prostate cancer cells, Exendin‑4 significantly decreased proliferation measured by BrdU assay.
In plain wordsIn cells, Exendin‑4 reduced prostate cancer cell proliferation.
Peptide
Exenatide (exendin-4)
Outcome
DecreaseCell proliferation
Study
n: not reported in source
Prostate cancer cells
Outcome group
Tumor growth · Cancer
Studied dose
Dose not stated
Source sentences
Summary
The BrdU assay revealed that both Exendin-4 and metformin significantly decreased prostate cancer cell proliferation.
Show in the study text Report a problemFND-2643962203
06LabIn vitro (cells)Mechanism
In LNCaP prostate cancer cells, Exendin‑4 did not activate AMPK.
In plain wordsIn cells, Exendin‑4 did not activate AMPK in prostate cancer cells.
Peptide
Exenatide (exendin-4)
Outcome
No significant changeAMPK activation
Study
n: not reported in source
LNCaP cells
Outcome group
Receptor activity and mechanism · Cancer
Studied dose
Dose not stated
Source sentences
Summary
Furthermore, metformin, but not Exendin-4, activated AMPK and induced apoptosis in LNCaP cells.
Show in the study text Report a problemFND-2643962204
07LabIn vitro (cells)Efficacy outcome
In LNCaP prostate cancer cells, Exendin‑4 did not induce apoptosis.
In plain wordsIn cells, Exendin‑4 did not induce prostate cancer cell death through apoptosis.
Peptide
Exenatide (exendin-4)
Outcome
No significant changeApoptosis
Study
n: not reported in source
LNCaP cells
Outcome group
Tumor growth · Cancer
Studied dose
Dose not stated
Source sentences
Summary
Furthermore, metformin, but not Exendin-4, activated AMPK and induced apoptosis in LNCaP cells.
Show in the study text Report a problemFND-2643962205

Studies that did not test the peptide alone5

In this study, Exenatide (exendin-4) was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Exenatide (exendin-4).

08AnimalNot a test of Exenatide (exendin-4) aloneAnimal study (in vivo)Efficacy outcome
In mice bearing prostate tumors, combined Exendin‑4 and metformin further reduced tumor size compared with Exendin‑4 alone.
In plain wordsIn mice with prostate tumors, Exendin‑4 combined with metformin reduced tumor size more than Exendin‑4 alone.
Peptide
Exenatide (exendin-4)
Outcome
DecreaseCombination tumor size versus Exendin-4
Study
mousen: not reported in source
Athymic mice bearing LNCaP tumors
Comparator
Exendin-4 alone
Outcome group
Tumor growth · Cancer
Source sentences
Summary
In vivo, Exendin-4 and metformin significantly decreased tumor size, and further significant tumor size reduction was observed after combined treatment.
1 context sentence(design, population, supporting numbers)
Summary · context
For in vivo experiments, LNCaP cells were transplanted subcutaneously into the flank region of athymic mice, which were then treated with Exendin-4 and/or metformin.
In this study, Exenatide (exendin-4) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Exenatide (exendin-4).
Show in the study text Report a problemFND-2643962208
09AnimalNot a test of Exenatide (exendin-4) aloneAnimal study (in vivo)Mechanism
In mice bearing prostate tumors, combined Exendin‑4 and metformin decreased tumor P504S expression.
In plain wordsIn mice with prostate tumors, Exendin‑4 combined with metformin decreased the tumor marker P504S.
Peptide
Exenatide (exendin-4)
Outcome
DecreaseCombination tumor P504S expression
Study
mousen: not reported in source
Athymic mice bearing LNCaP tumors
Outcome group
Tumor growth · Cancer
Source sentences
Summary
Immunohistochemistry on tumors revealed that the P504S and Ki67 expression decreased by Exendin-4 and/or metformin,
1 context sentence(design, population, supporting numbers)
Summary · context
For in vivo experiments, LNCaP cells were transplanted subcutaneously into the flank region of athymic mice, which were then treated with Exendin-4 and/or metformin.
In this study, Exenatide (exendin-4) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Exenatide (exendin-4).
Show in the study text Report a problemFND-2643962211
10AnimalNot a test of Exenatide (exendin-4) aloneAnimal study (in vivo)Mechanism
In mice bearing prostate tumors, combined Exendin‑4 and metformin decreased tumor Ki67 expression.
In plain wordsIn mice with prostate tumors, Exendin‑4 combined with metformin decreased the proliferation marker Ki67.
Peptide
Exenatide (exendin-4)
Outcome
DecreaseCombination tumor Ki67 expression
Study
mousen: not reported in source
Athymic mice bearing LNCaP tumors
Outcome group
Tumor growth · Cancer
Source sentences
Summary
Immunohistochemistry on tumors revealed that the P504S and Ki67 expression decreased by Exendin-4 and/or metformin,
1 context sentence(design, population, supporting numbers)
Summary · context
For in vivo experiments, LNCaP cells were transplanted subcutaneously into the flank region of athymic mice, which were then treated with Exendin-4 and/or metformin.
In this study, Exenatide (exendin-4) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Exenatide (exendin-4).
Show in the study text Report a problemFND-2643962212
11LabNot a test of Exenatide (exendin-4) aloneIn vitro (cells)Efficacy outcome
In prostate cancer cells, combined Exendin‑4 and metformin additively decreased cell growth.
In plain wordsIn cells, Exendin‑4 combined with metformin additively decreased prostate cancer growth.
Peptide
Exenatide (exendin-4)
Outcome
DecreaseCombination growth curve
Study
n: not reported in source
Prostate cancer cells
Outcome group
Tumor growth · Cancer
Source sentences
Summary
Exendin-4 and metformin additively decreased the growth curve, but not the migration, of prostate cancer cells.
In this study, Exenatide (exendin-4) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Exenatide (exendin-4).
Show in the study text Report a problemFND-2643962201
12LabNot a test of Exenatide (exendin-4) aloneIn vitro (cells)Efficacy outcome
In prostate cancer cells, combined Exendin‑4 and metformin did not decrease migration.
In plain wordsIn cells, Exendin‑4 combined with metformin did not decrease prostate cancer cell migration.
Peptide
Exenatide (exendin-4)
Outcome
No significant changeCombination migration
Study
n: not reported in source
Prostate cancer cells
Outcome group
Tumor growth · Cancer
Source sentences
Summary
Exendin-4 and metformin additively decreased the growth curve, but not the migration, of prostate cancer cells.
In this study, Exenatide (exendin-4) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Exenatide (exendin-4).
Show in the study text Report a problemFND-2643962202

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
22 Oct 2026, 02:26 UTC
Study results updated
Version 1
21 Oct 2026, 18:59 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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