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LY294002 and Metformin Cooperatively Enhance the Inhibition of Growth and the Induction of Apoptosis of Ovarian Cancer Cells
  1. Cuilan Li, MD*,
  2. Vincent Wing Sun Liu, PhD*,
  3. David Wai Chan, PhD*,
  4. Kwok Ming Yao, PhD and
  5. Hextan Yuen Sheung Ngan, MD*
  1. * Departments of Obstetrics and Gynecology, and
  2. Biochemistry, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, People’s Republic of China.
  1. Address correspondence and reprint requests to Hextan Yuen Sheung Ngan, MD, or Vincent Wing Sun Liu, PhD, Department of Obstetrics and Gynecology, The University of Hong Kong, 6th Floor, Professorial Block, Queen Mary Hospital, Pokfulam, Hong Kong SAR, People’s Republic of China. E-mail: hysngan{at}hkucc.hku.hk or vwsliu{at}hkusua.hku.hk.

Abstract

Background The phosphoinositide 3 kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT)/mammalian target of rapamycin (mTOR) pathway is frequently aberrantly activated in ovarian cancer and confers the chemoresistant phenotype of ovarian cancer cells. LY294002 (PI3K inhibitor) and metformin (5′-adenosine monophosphate [AMP]-activated protein kinase [AMPK] activator) are 2 drugs that were known to inhibit mTOR expression through the AKT-dependent and AKT-independent pathways, respectively. In this study, we explored the effectiveness of LY294002 and metformin in combination on inhibition of ovarian cancer cell growth.

Methods Western blotting was used to detect the changes of PI3K/AKT/mTOR and AMPK/acetyl-CoA carboxylase (ACC) signaling activities, cell cycle control, and apoptosis. Cell growth was evaluated by cell proliferation, colony formation, and soft agar assays. Flow cytometry was used to study cell cycle distribution and cell death upon drug treatment.

Results Our study showed that LY294002 and metformin in combination could simultaneously enhance the repression of the PI3K/AKT/mTOR pathway and the activation of the AMPK/ACC pathway. The downstream target of AKT and AMPK, mTOR, was cooperatively repressed when the drugs were used together. The cell cycle regulatory factors, p53, p27, and p21, were up-regulated. On the other hand, caspase 3 and poly (ADP-ribose) polymerase activities involved in apoptosis were also activated. Cell growth assays indicated that LY294002 and metformin could effectively inhibit ovarian cancer cell growth. Flow cytometry analysis showed that the treatment of the 2 drugs mentioned above induced cell cycle arrest at G1 phase and increased sub-G1 apoptotic cells.

Conclusion The combinational use of LY294002 and metformin can enhance inhibition of the growth and induction of the apoptosis of ovarian cancer cells. Our results may provide significant insight into the future therapeutic regimens in ovarian cancer.

  • LY294002
  • Metformin
  • AMPK
  • AKT
  • mTOR
  • Ovarian cancer

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Footnotes

  • The authors have no conflict of interest to declare.

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