Hyperthermic enhancement of the apoptotic and antiproliferative activities of paclitaxel

The antineoplastic agent paclitaxel (PTX), a microtubule-stabilizing agent, is known to arrest cell cycle progression and induce apoptosis. Mild hyperthermia (HT) also disrupts the microtubule system and triggers apoptosis. We therefore investigated whether concurrent exposure of murine breast cancer cells to 10 micromol/l PTX and 43 degrees C HT will promote improved anticancer effects. To do this, we exposed FM3A murine cancer cells to: (1) 10 micromol/l PTX for 1 h at 37 degrees C followed by exposure at 43 degrees C HT for 1 h; (2) 10 micromol/l PTX at 37 degrees C for 2 h; (3) 37 degrees C for 1 h followed by 43 degrees C HT for 1 h, and (4) untreated cells at 37 degrees C for 2 h which served as the control. Treatment No. 1 resulted in an enhanced cell cycle arrest, apoptosis and cytotoxicity. Exposure to 43 degrees C HT alone or 10 micromol/l PTX alone induced lesser apoptosis and cytotoxicity than the two treatments concurrently applied. The apoptotic cell death occurred in a time-dependent manner as follows: (1) concurrently applied 43 degrees C HT and 10 micromol/l PTX (5.6 +/- 0.5, 16.5 +/- 2 and 27.6 +/- 1%); (2) 43 degrees C HT alone (4.3 +/- 1, 6.6 +/- 0.3 and 12.7 +/- 1%) and (3) 10 micromol/l PTX alone (4.4 +/- 0.3, 8.6 +/- 1 and 12.8 +/- 1%) at 1, 6 and 24 h postexposure respectively compared to control of 2.0%. These data indicate that while both HT and PTX can individually induce apoptosis and antiproliferation in FM3A cancer cells, they may offer synergistic benefits when used concurrently.