Platinum-based combination chemotherapy triggers cancer cell death through induction of BNIP3 and ROS, but not autophagy

J Cell Mol Med. 2020 Jan;24(2):1993-2003. doi: 10.1111/jcmm.14898. Epub 2019 Dec 19.


These days, cancer can still not be effectively cured because cancer cells readily develop resistance to anticancer drugs. Therefore, an effective combination of drugs with different mechanisms to prevent drug resistance has become a very important issue. Furthermore, the BH3-only protein BNIP3 is involved in both apoptotic and autophagic cell death. In this study, lung cancer cells were treated with a chemotherapy drug alone or in combination to identify the role of BNIP3 and autophagy in combination chemotherapy for treating cancer. Our data revealed that various combinational treatments of two drugs could increase cancer cell death and cisplatin in combination with rapamycin or LBH589, which triggered the cell cycle arrest at the S phase. Cells with autophagosome and pEGFP-LC3 puncta increased when treated with drugs. To confirm the role of autophagy, cancer cells were pre-treated with the autophagy inhibitor 3-methyladenine (3-MA). 3-MA sensitized cancer cells to chemotherapy drug treatments. These results suggest that autophagy may be responsible for cell survival in combination chemotherapy for lung cancer. Moreover, BNIP3 was induced and localized in mitochondria when cells were treated with drugs. The transfection of a dominant negative transmembrane deletion construct of BNIP3 (BNIP3ΔTM) and treatment of a reactive oxygen species (ROS) inhibitor suppressed chemo drug-induced cell death. These results indicate that BNIP3 and ROS may be involved in combination chemo drug-induced cell death. However, chemo drug-induced autophagy may protect cancer cells from drug cytotoxicity. As a result, inhibiting autophagy may improve the effects of combination chemotherapy when treating lung cancer.

Keywords: BNIP3; autophagy; combination chemotherapy; reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Autophagy* / drug effects
  • Cell Death / drug effects
  • Drug Therapy, Combination
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology*
  • Membrane Proteins / metabolism*
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondrial Membranes / drug effects
  • Mitochondrial Membranes / metabolism
  • Models, Biological
  • Platinum / pharmacology
  • Platinum / therapeutic use*
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins / metabolism*
  • Reactive Oxygen Species / metabolism*


  • Antineoplastic Agents
  • BNIP3 protein, human
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Reactive Oxygen Species
  • Platinum
  • 3-methyladenine
  • Adenine