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Correspondence re: M. Fanciulli et al., Energy Metabolism of Human LoVo Colon Carcinoma Cells: Correlation to Drug Resistance and Influence of Lonidamine. Clin. Cancer Res., 6: 1590–1597, 2000.

Department of Surgery A, Tel-Aviv Medical Center, 6 Weizman Street, Tel-Aviv 64239, Israel

ABSTRACT

The relationship between energy metabolism and multidrug resistance of cancer cells was described recently by Fanciulli et al (1) . The authors found that the anticancer drug LND¹ almost completely inhibited doxorubicin extrusion by resistant human colon cancer cells and reduced drug resistance. These data may be relevant to cancer therapy because multidrug resistance, as the authors stated, is one of the main reasons for treatment failure. To optimize the effects of a drug, its mechanism of action should be delineated. In this regard, Fanciulli et al. (1) referred to our previous studies (2 , 3) on the mechanism of action of LND and mentioned that we found that LND administration was associated with a lower extracellular content of lactate. However, it should be noted that our principal finding was that LND treatment was followed by an early, remarkable elevation of intracellular lactate, and this phenomenon was found in multiple cancer cell lines. Fanciulli et al. (1) argued that the primary effect of LND was inhibition of glycolysis. However, inhibition of glycolysis should be followed by reduced levels of its end product; therefore, their statement is not consistent with the data. Concomitant with the remarkable elevation of intracellular lactate, its extracellular level was indeed lower than that in the controls, and the only possible explanation for these findings is inhibition of lactate efflux. The molecular structure of LND is similar to that of compounds known as lactate transport inhibitors. We suggest that the primary mechanism of action of LND is intracellular acidification due to inhibition of lactate efflux and that this effect is followed by secondary impairments of enzymatic (including mitochondria-bound hexokinase) processes.

FOOTNOTES

¹ The abbreviation used is: LND, lonidamine.

Received 6/20/00; accepted 7/26/00.

REFERENCES

1. Fanciulli, M., Bruno, T., Giovannelli, A., Gentile, F. P., Di Padova, M., Rubiu, O., and Floridi, A. Energy metabolism of human LoVo colon carcinoma cells: correlation to drug resistance and influence of lonidamine. Clin. Cancer Res. 6: 1590–1597, 2000.
2. Ben-Horin H., Tassini M., Vivi A., Navon G., Kaplan O. Mechanism of action of the anti-neoplastic agent lonidamine—NMR studies. Cancer Res., 55: 2814-2821, 1995.[Abstract/Free Full Text]
3. Vivi A., Tassini M., Ben-Horin H., Navon G., Kaplan O. Effects and comparison of action of the anti-neoplastic drug lonidamine on drug-sensitive and drug-resistant human breast cancer cells: ³¹P and ¹³C nuclear magnetic resonance studies. Breast Cancer Res. Treat., 43: 15-25, 1997.[CrossRef][Medline]

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