PARENT SESSION

Experimental and Clinical Therapeutics

(PP101) Acute acidification reduces the heat shock response and sensitizes human melanoma cells grown at low pH to thermal therapy.

Storck, Christopher¹, Wahl, Miriam², Leeper, Dennis¹, Coss, Ronald^*,1, ¹ Department of Radiation Oncology, Philadelphia, PA, USA² Department of Pathology, Durham, NC, USA

ABSTRACT- SK-Mel-28 and DB-1 human melanoma cells grown at pH 7.3 have a critical intracellular pH (pHi) threshold below which they become sensitized to 42°C, while cells grown at pH 6.7 are already at or near their critical pHi threshold. Consequently, it takes less of a reduction in extracellular pH (pHe) to reduce pHi and selectively sensitize these cells grown at pH 6.7 to thermal therapy. We examined whether or not DB-8 human melanoma cells have pHi thresholds for thermal sensitization. Furthermore, in contrast to SK-Mel-28 and DB-1 cells, the endogenous levels of Hsp27 in DB-8 cells cultured at pH 6.7 is 60-fold less than in cells cultured at pH 7.3. A pHi threshold was found to exist for DB-8 cells cultured at pH 7.3 below which they became sensitized to 42°C. A pHi threshold for heat sensitization did not exist for cells growing at pH 6.7: any reduction in pHi prior to heating resulted in increased cell killing. There was a greater decrease in pHi per unit decrease in pHe for cells grown at pH 6.7. Consequently, DB-8 cells grown at pH 6.7 are sensitized more to 42°C per unit decrease in pHi (and pHe) than cells grown at pH 7.3. Acute acidification abrogated the 42°C-induction of Hsp70 and Hsp27 in the DB-8 cells. The pHi thresholds for abrogation of HSP induction are higher than the pHi thresholds for thermal sensitization of cells grown at pH 7.3. A pHi threshold did not exist for abrogation of HSP induction in cells cultured at pH 6.7. These findings support the concept for sensitization of human melanoma cells to thermal therapy by strategies that selectively lower the pHi in cells existing in an acidic environment. (Funded by Grant No. PO1 CA56690 from NCI, NIH, DHHS).

Key words: thermal sensitization, pHi threshold, human melanoma cells, heat shock proteins