Overcoming the radioresistance of Bcl-2 overexpressing tumor cells with heavy-ion irradiation

Abstract

High-LET heavy ions have been used clinically to cure malignant tumors not merely because of their excellent spatial dose distribution but because of their greater biological effectiveness compared to low-LET radiations. We have here investigated the potential impact of heavy-ion irradiation on the radioresistance of tumor cells overexpressing Bcl-2. While Bcl-2 overexpressing HeLa (HeLa/bcl-2) cells were more resistant to gamma-rays (0.2 keV/μm) and helium ions (16 keV/μm) than neomycin resistance gene expressing HeLa (HeLa/neo) cells, there was very little if any difference in susceptibility to heavy ions (76-1610 keV/μm) between HeLa/neo and HeLa/bcl-2 cells. This suggests that high-LET heavy ions overcome the radioresistance caused by Bcl-2 overexpression. Besides, after exposure to carbon ions (108 keV/μm) whose RBE was maximal among six different beams of heavy ions tested, the yield of apoptosis was lower but G2/M arrest was more prolonged in HeLa/bcl-2 than in Hela/neo cells. This result highlights that Bcl-2, in addition to its well-known anti-apoptotic function, may participate in G2/M checkpoint after heavy-ion irradiation. Clarification of the molecular underpinnings of Bcl-2 mediated G2/M checkpoint encourages further studies.