Mechanism of action of lonidamine in the 9L brain tumor model involves inhibition of lactate efflux and intracellular acidification
Mechanism of action of lonidamine in the 9L brain tumor model involves inhibition of lactate efflux and intracellular acidification
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DOI：
10.1023/a:1005819604858
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发表时间：
1998-01-01
影响因子：
3.9
通讯作者：
Ross, BD
中科院分区：
文献类型：
--
作者：
Ben-Yoseph, O;Lyons, JC;Ross, BD
恶性神经胶质瘤与高速率的糖酵解活性相关，这被认为是维持细胞功能和完整性所必需的。由于氯尼达明（LND）被认为是通过抑制糖酵解酶己糖激酶（HK）来减少肿瘤葡萄糖的利用，P-31磁共振波谱（MRS）被用于非侵入性地跟踪LND对皮下大鼠9 L胶质瘤中肿瘤pH和高能磷酸盐代谢产物ATP、磷酸肌酸（PCr）和无机磷酸盐（P-i）的影响。在50和100 mg/kg LND腹膜内给药前和给药后5 min间隔内采集的P-31肿瘤光谱显示，给药后30 min内酸中毒pH值分别变化-0.25和-0.45 pH单位。9 L肿瘤的ATP/Pi比率在3小时内降低至对照的40%，并且Pi水平增加至对照的280%。LND对肿瘤血流量和平均动脉压无明显影响。脑和肌肉代谢物水平和pH值也不受LND的影响。体外培养的9 L肿瘤细胞内和细胞外乳酸、磷酸戊糖途径（PPP）和己糖激酶（HK）活性的测定表明，LND的作用方式涉及抑制乳酸流出和细胞内酸化。通过LND选择性降低肿瘤能量代谢物和pH可用于使胶质瘤对放射、化学疗法或热疗敏感。
Malignant gliomas have been associated with a high rate of glycolytic activity which is believed necessary to sustain cellular function and integrity. Since lonidamine (LND) is believed to reduce tumor glucose utilization by inhibition of the mitochondrially-bound glycolytic enzyme hexokinase (HK), P-31 magnetic resonance spectroscopy (MRS) was used to noninvasively follow the effects of LND on both tumor pH and the high-energy phosphate metabolites; ATP, phosphocreatine (PCr) and inorganic phosphate (P-i) in subcutaneous rat 9L gliosarcomas. P-31 tumor spectra acquired in 5 min intervals pre-and post LND administration of 50 and 100 mg/kg, i.p. revealed an acidotic pH shift of -0.25 and -0.45 pH units, respectively within 30 min post administration. The ATP/P-i ratio of 9L tumors decreased to 40% of control and P-i levels increased to 280% of control over a 3 hr period. LND exerted no effect on tumor blood flow and mean arterial blood pressure. Brain and muscle metabolite levels and pH were also unaffected by LND. In vitro measurements of cultured 9L tumor cell intra-and extracellular lactate, pentose phosphate pathway (PPP) and hexokinase (HK) activities suggest that the mode of action of LND involves inhibition of lactate efflux and intracellular acidification. The selective reduction of tumor energy metabolites and pH by LND may be exploitable for sensitizing gliomas to radiation, chemotherapy or hyperthermia.