Vivi A, Tassini M, Ben-Horin H, Navon G, Kaplan O
School of Chemistry, Tel-Aviv University, Israel.
Breast Cancer Res Treat. 1997 Mar;43(1):15-25. doi: 10.1023/a:1005781320906.
Lonidamine (LND) is a relatively new anti-cancer drug, and several clinical trials have indicated that it may be effective in combinations with other therapeutic modalities. LND is classified within the metabolic inhibitor agents. Multidrug resistance (MDR) phenomenon is often associated with increased energy requirements, and enhanced glycolysis rate. These studies were performed to delineate the mechanism of action of LND on MDR human breast cancer cells, and to investigate whether LND as a single agent, or in combination with another anti-metabolism drug, 2-deoxyglucose (2-DG), may be useful against MDR tumors. The effects of LND on intact perfused drug-sensitive (WT) and 33-fold resistant to Adriamycin (Adr) MCF-7 cells, embedded in alginate micro capsules, were continuously monitored by 31P and 13C nuclear magnetic resonance (NMR) spectroscopy. 31P NMR studies showed that LND induced intracellular acidification and depletion of NTP in both WT and Adr cells. However, pH and NTP levels decreased less in the Adr cells than in the WT cells (p < 0.05 for both parameters). 13C NMR demonstrated that LND inhibited lactate transport, and lactate signals were elevated in both cell lines. However, the intracellular lactate levels increased to a greater extent in the WT than in the Adr cells (p < 0.05). There were major differences in the effects of LND on metabolism between sensitive and resistant cells. While LND enhanced glucose uptake in the WT cells, and its administration was followed by continuous increase of lactate signal, both processes were not affected by LND in the Adr cells. 2-DG is a glucose analogue that inhibits both cellular uptake and utilization of glucose, leading to cell starvation. Combined treatment with LND and 2-DG yielded at best additive, but not synergistic, cellular toxicity, and the metabolic effects of LND were attenuated by 2-DG. These results showed that the principal mechanism of action of LND is inhibition of lactate transport leading to intracellular lactate accumulation and acidification in both WT and Adr cells. The Adr cells were only 2-fold resistant to LND (compared to the WT cells), and since cellular uptake of alkaloid chemotherapy is improved in acidic environment, LND may have a role in the treatment protocols of MDR tumors, especially when given as the initial means for induction of intracellular acidification.
氯尼达明（LND）是一种相对较新的抗癌药物，多项临床试验表明它与其他治疗方式联合使用可能有效。LND属于代谢抑制剂类药物。多药耐药（MDR）现象通常与能量需求增加和糖酵解速率提高有关。进行这些研究是为了阐明LND对MDR人乳腺癌细胞的作用机制，并研究LND作为单一药物或与另一种抗代谢药物2-脱氧葡萄糖（2-DG）联合使用是否对MDR肿瘤有效。通过31P和13C核磁共振（NMR）光谱连续监测LND对包埋在藻酸盐微胶囊中的完整灌注的药物敏感（WT）和对阿霉素（Adr）耐药33倍的MCF-7细胞的影响。31P NMR研究表明，LND诱导WT细胞和Adr细胞内酸化和NTP消耗。然而，Adr细胞中pH和NTP水平的下降幅度小于WT细胞（两个参数的p均<0.05）。13C NMR表明，LND抑制乳酸转运，两种细胞系中的乳酸信号均升高。然而，WT细胞内乳酸水平的升高幅度大于Adr细胞（p<0.05）。LND对敏感细胞和耐药细胞代谢的影响存在主要差异。虽然LND增强了WT细胞对葡萄糖的摄取，且给药后乳酸信号持续增加，但在Adr细胞中这两个过程均不受LND影响。2-DG是一种葡萄糖类似物，可抑制细胞对葡萄糖的摄取和利用，导致细胞饥饿。LND和2-DG联合治疗产生的细胞毒性充其量只是相加作用，而非协同作用，且2-DG减弱了LND的代谢作用。这些结果表明，LND的主要作用机制是抑制乳酸转运，导致WT细胞和Adr细胞内乳酸积累和酸化。Adr细胞对LND的耐药性仅为WT细胞的2倍（与WT细胞相比），并且由于在酸性环境中生物碱化疗药物的细胞摄取会增加，LND可能在MDR肿瘤的治疗方案中发挥作用，尤其是作为诱导细胞内酸化的初始手段时。
