Cadmium-induced inhibition of the growth and metastasis of human lung carcinoma xenografts: role of apoptosis

Our previous studies indicate that cadmium in mice can inhibitthe formation of chemically induced and spontaneously occurringtumors in the liver and lung. Cadmium is an effective anti-tumoragent when given at non-toxic doses and even when given wellafter tumor formation, implying a unique sensitivity in certaintumor cells. The present studies tested the ability of cadmiumto inhibit growth and progression of transplanted human pulmonarytumor xenografts. Male athymic nude mice were inoculated witheither H460 cells, originally derived from a non-small cellpulmonary carcinoma, or DMS 114 cells, originally derived froma small cell lung carcinoma, under the left renal capsule. Starting1 week later mice received 0, 125 or 250 p.p.m. cadmium in thedrinking water, levels without effect on host animal growthor survival, and were observed over the next 4 weeks (H460 cells)or 100 days (DMS 114 cells). An additional experiment gave cadmiumas an i.v. loading dose (20 µmol/kg) 4 days after renalinoculation with H460 cells and 200 p.p.m. cadmium in the drinkingwater from 7 days onward, with an observation period of 28 days.Cadmium caused dose-related reductions in the growth of tumorsresulting from the inoculation of either H460 or DMS 114 cellsof up to 83%. Additionally, cadmium reduced the rate of tumormetastasis to the lung by up to 58%. Cadmium treatment had noeffects on either Bcl-2 or Bax protein expression in tumor xenografts,indicating that apoptotic pathways probably do not contributeto this anti-neoplastic effect. These studies show cadmium caneffectively reduce growth and progression of human lung carcinomaxenografts in a fashion that is probably independent of apoptosis.