Increasing the rate of heating: a potential therapeutic approach for achieving synergistic tumour killing in combined hyperthermia and chemotherapy

Int J Hyperthermia. 2013;29(2):145-55. doi: 10.3109/02656736.2012.760757. Epub 2013 Jan 25.


Purpose: A synergistic cancer cell killing effect of sub-lethal hyperthermia and chemotherapy has been reported extensively. In this study, in vitro cell culture experiments with a uterine cancer cell line (MES-SA) and its multidrug resistant (MDR) variant MES-SA/Dx5 were conducted in order to investigate the role of heating rate in achieving a synergistic effect. The mode of cell death, induction of thermal tolerance and P-glycoprotein (P-gp) mediated MDR following two different rates of heating were studied.

Materials and methods: Doxorubicin (DOX) was used as the chemotherapy drug. A rapid rate hyperthermia was achieved by near infrared laser (NIR) excited indocyanine green (ICG) dye (absorption maximum at 808 nm, ideal for tissue penetration). A slow rate hyperthermia was provided by a cell culture incubator.

Results: The potentiating effect of hyperthermia to chemotherapy can be maximised by increasing the rate of heating. When delivered at the same thermal dose, a rapid increase in temperature from 37°C to 43°C caused more cell membrane damage than gradually heating the cells from 37°C to 43°C and thus allowed for more intracellular accumulation of DOX. Meanwhile, the rapid rate laser-ICG hyperthermia at 43°C caused cell necrosis whereas the slow rate incubator hyperthermia at 43°C induced mild apoptosis. At 43°C a positive correlation between thermal tolerance and the length of hyperthermia exposure is identified.

Conclusions: This study shows that by increasing the rate of heating, less thermal dose is needed in order to overcome P-gp mediated MDR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Apoptosis
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Combined Modality Therapy / methods
  • Doxorubicin / therapeutic use*
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Female
  • HSP70 Heat-Shock Proteins / biosynthesis
  • Humans
  • Hyperthermia, Induced / methods*
  • Necrosis
  • Uterine Neoplasms / therapy*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • HSP70 Heat-Shock Proteins
  • Doxorubicin
  • Caspase 3