EXTH-74. MOLECULAR MECHANISMS OF ANTI-TUMOR ACTION OF TTFIELDS DETERMINED BY MEASUREMENTS AND MODELING OF ELECTRO-CONDUCTIVE PROPERTIES OF MICROTUBULES

Biological effects of AC electric fields at frequencies between 100–300 kHz discovered a decade ago are being applied to cancer cells as a therapeutic modality in the treatment of glioblastoma multiforme (GBM). They are called Tumor Treating Fields (TTFields) as they disrupt cell division. Based on our electro-conductive measurements and modeling, we provide an assessment of possible molecular-level mechanisms. Computer simulations and experimental measurements carried out for microtubules and actin filaments are presented. Charge and dipole values for monomers and dimers as well as polymerized forms of these proteins are summarized. Continuum approximations for cable equations describing actin filaments and microtubules compare favorably to measurements in buffer solutions showing soliton waves and transistor-like amplification of ionic signals, respectively. AC Conductivity and capacitance of tubulin and microtubules have been measured and modeled in the range of frequencies between 100 kHz and 1 MHz. A dramatic change in conductivity occurs when tubulin forms microtubules. In living cells, this signals a conductive phase transition coinciding with mitosis in dividing cells. This process is allowed by TTField penetration into the cleavage furrow in dividing cells and provides the most significant mechanistic explanation of the observed effects. We provide estimates of the forces, energies and power involved in the action of TTFields on microtubules and kinesin motors. These calculations are compared and contrasted with typical values experienced at a cell level and provide strong arguments for real physical effects of TTFields in dividing cells. We also show results of DLS and TEM measurements on microtubules and tubulin oligomers in solution, which allow us to quantify these processes under controlled conditions. In conclusion, the most likely candidates to provide a quantitative explanation of these effects are ionic condensation waves around microtubules as well as dielectrophoretic effects on the dipole moments of microtubules.