Metformin as an adjuvant drug against pediatric sarcomas: Hypoxia limits therapeutic effects of the drug

Cecilia Garofalo, Mariantonietta Capristo, Maria Cristina Manara, Caterina Mancarella, Lorena Landuzzi, Antonino Belfiore, Pier Luigi Lollini, Piero Picci, Katia Scotlandi

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Metformin, a well-known insulin-sensitizer commonly used for type 2 diabetes therapy, has recently emerged as potentially very attractive drug also in oncology. It is cheap, it is relatively safe and many reports have indicated effects in cancer prevention and therapy. These desirable features are particularly interesting for pediatric sarcomas, a group of rare tumors that have been shown to be dependent on IGF and insulin system for pathogenesis and progression. Metformin exerts antimitogenic activity in several cancer histotypes through several molecular mechanisms. In this paper, we analyzed its effects against osteosarcoma, Ewing sarcoma and rhabdomyosarcoma, the three most common pediatric sarcomas. Despite in vitro metformin gave remarkable antiproliferative and chemosensitizing effects both in sensitive and chemoresistant cells, its efficacy was not confirmed against Ewing sarcoma xenografts neither as single agent nor in combination with vincristine. This discrepancy between in vitro and in vivo effects may be due to hypoxia, a common feature of solid tumors. We provide evidences that in hypoxia conditions metformin was not able to activate AMPK and inhibit mTOR signaling, which likely prevents the inhibitory effects of metformin on tumor growth. Thus, although metformin may be considered a useful complement of conventional chemotherapy in normoxia, its therapeutic value in highly hypoxic tumors may be more limited. The impact of hypoxia should be considered when novel therapies are planned for pediatric sarcomas.

Original languageEnglish
Article numbere83832
JournalPLoS One
Volume8
Issue number12
DOIs
Publication statusPublished - Dec 31 2013

Fingerprint

drug adjuvants
metformin
Pediatrics
Metformin
sarcoma
Therapeutic Uses
Sarcoma
hypoxia
drugs
therapeutics
neoplasms
Tumors
Pharmaceutical Preparations
Neoplasms
Ewing's Sarcoma
insulin
Insulin
vincristine
AMP-Activated Protein Kinases
Oncology

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Metformin as an adjuvant drug against pediatric sarcomas : Hypoxia limits therapeutic effects of the drug. / Garofalo, Cecilia; Capristo, Mariantonietta; Manara, Maria Cristina; Mancarella, Caterina; Landuzzi, Lorena; Belfiore, Antonino; Lollini, Pier Luigi; Picci, Piero; Scotlandi, Katia.

In: PLoS One, Vol. 8, No. 12, e83832, 31.12.2013.

Research output: Contribution to journalArticle

@article{3a1ede0e833642b085cef830f5e6ea06,
title = "Metformin as an adjuvant drug against pediatric sarcomas: Hypoxia limits therapeutic effects of the drug",
abstract = "Metformin, a well-known insulin-sensitizer commonly used for type 2 diabetes therapy, has recently emerged as potentially very attractive drug also in oncology. It is cheap, it is relatively safe and many reports have indicated effects in cancer prevention and therapy. These desirable features are particularly interesting for pediatric sarcomas, a group of rare tumors that have been shown to be dependent on IGF and insulin system for pathogenesis and progression. Metformin exerts antimitogenic activity in several cancer histotypes through several molecular mechanisms. In this paper, we analyzed its effects against osteosarcoma, Ewing sarcoma and rhabdomyosarcoma, the three most common pediatric sarcomas. Despite in vitro metformin gave remarkable antiproliferative and chemosensitizing effects both in sensitive and chemoresistant cells, its efficacy was not confirmed against Ewing sarcoma xenografts neither as single agent nor in combination with vincristine. This discrepancy between in vitro and in vivo effects may be due to hypoxia, a common feature of solid tumors. We provide evidences that in hypoxia conditions metformin was not able to activate AMPK and inhibit mTOR signaling, which likely prevents the inhibitory effects of metformin on tumor growth. Thus, although metformin may be considered a useful complement of conventional chemotherapy in normoxia, its therapeutic value in highly hypoxic tumors may be more limited. The impact of hypoxia should be considered when novel therapies are planned for pediatric sarcomas.",
author = "Cecilia Garofalo and Mariantonietta Capristo and Manara, {Maria Cristina} and Caterina Mancarella and Lorena Landuzzi and Antonino Belfiore and Lollini, {Pier Luigi} and Piero Picci and Katia Scotlandi",
year = "2013",
month = "12",
day = "31",
doi = "10.1371/journal.pone.0083832",
language = "English",
volume = "8",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "12",

}

TY - JOUR

T1 - Metformin as an adjuvant drug against pediatric sarcomas

T2 - Hypoxia limits therapeutic effects of the drug

AU - Garofalo, Cecilia

AU - Capristo, Mariantonietta

AU - Manara, Maria Cristina

AU - Mancarella, Caterina

AU - Landuzzi, Lorena

AU - Belfiore, Antonino

AU - Lollini, Pier Luigi

AU - Picci, Piero

AU - Scotlandi, Katia

PY - 2013/12/31

Y1 - 2013/12/31

N2 - Metformin, a well-known insulin-sensitizer commonly used for type 2 diabetes therapy, has recently emerged as potentially very attractive drug also in oncology. It is cheap, it is relatively safe and many reports have indicated effects in cancer prevention and therapy. These desirable features are particularly interesting for pediatric sarcomas, a group of rare tumors that have been shown to be dependent on IGF and insulin system for pathogenesis and progression. Metformin exerts antimitogenic activity in several cancer histotypes through several molecular mechanisms. In this paper, we analyzed its effects against osteosarcoma, Ewing sarcoma and rhabdomyosarcoma, the three most common pediatric sarcomas. Despite in vitro metformin gave remarkable antiproliferative and chemosensitizing effects both in sensitive and chemoresistant cells, its efficacy was not confirmed against Ewing sarcoma xenografts neither as single agent nor in combination with vincristine. This discrepancy between in vitro and in vivo effects may be due to hypoxia, a common feature of solid tumors. We provide evidences that in hypoxia conditions metformin was not able to activate AMPK and inhibit mTOR signaling, which likely prevents the inhibitory effects of metformin on tumor growth. Thus, although metformin may be considered a useful complement of conventional chemotherapy in normoxia, its therapeutic value in highly hypoxic tumors may be more limited. The impact of hypoxia should be considered when novel therapies are planned for pediatric sarcomas.

AB - Metformin, a well-known insulin-sensitizer commonly used for type 2 diabetes therapy, has recently emerged as potentially very attractive drug also in oncology. It is cheap, it is relatively safe and many reports have indicated effects in cancer prevention and therapy. These desirable features are particularly interesting for pediatric sarcomas, a group of rare tumors that have been shown to be dependent on IGF and insulin system for pathogenesis and progression. Metformin exerts antimitogenic activity in several cancer histotypes through several molecular mechanisms. In this paper, we analyzed its effects against osteosarcoma, Ewing sarcoma and rhabdomyosarcoma, the three most common pediatric sarcomas. Despite in vitro metformin gave remarkable antiproliferative and chemosensitizing effects both in sensitive and chemoresistant cells, its efficacy was not confirmed against Ewing sarcoma xenografts neither as single agent nor in combination with vincristine. This discrepancy between in vitro and in vivo effects may be due to hypoxia, a common feature of solid tumors. We provide evidences that in hypoxia conditions metformin was not able to activate AMPK and inhibit mTOR signaling, which likely prevents the inhibitory effects of metformin on tumor growth. Thus, although metformin may be considered a useful complement of conventional chemotherapy in normoxia, its therapeutic value in highly hypoxic tumors may be more limited. The impact of hypoxia should be considered when novel therapies are planned for pediatric sarcomas.

UR - http://www.scopus.com/inward/record.url?scp=84896714232&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84896714232&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0083832

DO - 10.1371/journal.pone.0083832

M3 - Article

C2 - 24391834

AN - SCOPUS:84896714232

VL - 8

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 12

M1 - e83832

ER -