Suppression of manganese superoxide dismutase augments sensitivity to radiation, hyperthermia and doxorubicin in colon cancer cell lines by inducing apoptosis

Increased expression of manganese superoxide dismutase (Mn-SOD), one of the mitochondrial enzymes involved in the redox system, has been shown to diminish the cytotoxic effects of several anti-cancer modalities, including tumour necrosis factor-alpha, ionizing radiation, certain chemotherapeutic agents and hyperthermia. We asked if Mn-SOD is a potential target to augment the sensitivity of cancer cells to various anti-cancer treatments and for this we established stable Mn-SOD antisense RNA expressing cell clones from two human colon cancer cell lines, HCT116 (p53 wild-type) and DLD1 (p53 mutant-type). Suppression of Mn-SOD in HCT116 was accompanied by an increased sensitivity to radiation, hyperthermia and doxorubicin, as compared with findings in controls. The mitochondrial permeability transition, as measured by a decrease of the mitochondrial transmembrane potential was more intensely induced by radiation in HCT116 antisense clones than in the control, an event followed by a greater extent of DNA fragmentation. Apoptosis was also induced by hyperthermia more intensely in HCT116 antisense clones than in the control. On the other hand, DLD1 antisense clones did not exhibit any enhancement of sensitivity to any of these treatments. These data support the possibility that inhibition of Mn-SOD activity renders colon cancer cells with wild-type p53 susceptible to apoptosis induced by radiation, hyperthermia and selected anti-cancer drugs. Therefore, we suggest that Mn-SOD could be a target molecule to overcome the resistance to anti-cancer treatments in some colon cancer cells carrying wild-type p53. (C) 2000 Cancer Research Campaign.