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 dimi nish the cytotoxic effects of several anti-cancer modalities, including tum our necrosis factor-alpha, ionizing radiation, certain chemotherapeutic age nts and hyperthermia. We asked if Mn-SOD is a potential target to augment t he sensitivity of cancer cells to various anti-cancer treatments and for th is we established stable Mn-SOD antisense RNA expressing cell clones from t wo human colon cancer cell lines, HCT116 (p53 wild-type) and DLD1 (p53 muta nt-type). Suppression of Mn-SOD in HCT116 was accompanied by an increased s ensitivity to radiation, hyperthermia and doxorubicin, as compared with fin dings in controls. The mitochondrial permeability transition, as measured b y a decrease of the mitochondrial transmembrane potential was more intensel y induced by radiation in HCT116 antisense clones than in the control, an e vent followed by a greater extent of DNA fragmentation. Apoptosis was also induced by hyperthermia more intensely in HCT116 antisense clones than in t he control. On the other hand, DLD1 antisense clones did not exhibit any en hancement 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, hyperther mia 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.