SCience

The Biological Mechanisms of Scalp Cooling

Biological research on scalp cooling, has been focused on exploring the hypothesis that cooling reduces the entry of chemotherapy drugs into human keratinocytes.[1]

Research carried out by Dunnill et al., found that cooling can reduce drug uptake by a minimum of ~4 fold, and this can increase up to ~8 fold depending on the cell model used or drug tested.[2] This outcome is due to a number of identified mechanisms which occur as a result of scalp cooling.

The Four Mechanisms of Scalp Cooling

It has been determined that the following mechanisms of scalp cooling, when occurring in combination, renders cooling of the scalp cytoprotective - contributing to reported clinical efficacy when used in conjunction with chemotherapy treatment[1] for solid tumour cancers. Having a better understanding of the cellular mechanisms by which cooling reduces the chemotoxicity of rapidly dividing cells allows us to both predict which chemotherapy regimens scalp cooling will be less effect for and find solutions to increase its efficacy.

Previously, it was thought that vasoconstriction was the only mechanism in which scalp cooling reduced the cytotoxicity of chemotherapy drugs, however further in vitro experiments have revealed other protective effects – such as reduced drug uptake, reduced metabolic activity, and reduced rate of hair follicle cell division

Vasoconstriction
Reduced Drug Uptake
Reduced Hair Follicle Cell Division
Reduced Metabolic Activity
Vasoconstriction
  • Scalp cooling induces vasoconstriction
  • Cutaneous drug perfusion reduces to 20-40% of normal levels
  • Chemotherapy drug perfusion reduces through the hair follicle
Non-cooled

Vasoconstriction in Detail

  • As the temperature of the cooling cap is significantly lower than the skin’s normal temperature, scalp cooling triggers vasoconstriction and consequently a reduction in blood (flow) perfusion to between 20-40% of normal blood flow levels

  • Reduction of blood flow translates to reduction in the extent of drug exposure, and therefore hair follicle damage overall

Cooled

Reduced drug uptake into the hair follicle cell

The rate of drug uptake across the plasma membrane is reduced at low temperature, due to:

  • Reduction of active transport or reduced diffusion of cytotoxic drug

As a result of:

  • Lower hair follicle cellular activity
  • Reduced kinetic energy and membrane fluidity
Non-cooled

Reduced Drug Uptake in Detail

  • Active transport via membrane proteins, as well as passive diffusion, are the processes by which chemotherapy drugs (such as the anthracycline doxorubicin) enter the cell via the cell membrane
  • Low temperatures can cause a significant reduction in active transport, as transport is an energy (and thus metabolism)-dependent process
  • Hypothermia can also reduce membrane fluidity because lowering the temperature causes structural changes to the plasma membrane and this can dramatically reduce its permeability for chemotherapy drugs
  • As cooling suppresses both of these possible mechanisms by which drugs enter the hair follicles, it is able to cause a marked reduction in cellular drug uptake
  • The above has been demonstrated through biological studies using cell cultures, taken from the proliferative sub-population of cells of the hair follicles
Cooled

Reduced rate of hair follicle cell division

  • Cell division is an energy-dependent process
  • Cooling may slow the rate of this division, thus making these cells less susceptible to being targeted by the chemotherapy drugs
Non-cooled

Reduced Cell Division in Detail

  • During the active phase of hair follicle growth, the cells in the follicles, continually stimulated by growth factors, are thus in a highly-proliferative state. As a consequence, these cells are more vulnerable to the cytotoxic effect of chemotherapy drugs

  • Cooling reduces the metabolic activity of cells and as a consequence, the rate of cell division is reduced, which renders these cells of the hair follicles less susceptible to being targeted by the chemotherapy drugs

  • This is especially important for chemotherapy drugs that target specific phases of the cell cycle, such as mitosis-targeting microtubule-destructive drugs (taxanes).

Cooled
Reduced metabolic activity
  • In addition to mitosis, cooling reduces the metabolic rate of cells, and therefore a range of cellular processes decelerate – such as oxidisation
Non-cooled
Reduced Metabolic Activity in Detail
  • The myriad of biological reactions that take place inside cells, such as metabolism, cell growth and cell death, is catalysed by enzymes - which are acutely temperature-dependent
  • A reduction in temperature may thus cause deceleration of cellular processes that can be involved in chemotherapy drug-mediated cytotoxicity – mainly the generation of reactive oxygen species, oxidative damage, and ultimately, cellular destruction. The deceleration of these processes could help attenuate toxicity and hair follicle damage
Cooled

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Footnotes

[1] Dunnill et al. Cooling-mediated protection from chemotherapy drug-induced cytotoxicity in human keratinocytes by inhibition of cellular drug uptake. PLoS One. 2020 Oct 15;15(10):e0240454. Page 3

[2] Dunnill et al. Cooling-mediated protection from chemotherapy drug-induced cytotoxicity in human keratinocytes by inhibition of cellular drug uptake. PLoS One. 2020 Oct 15;15(10):e0240454. Page 10

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