Cancer cells have a very different metabolism from that of normal cells from which they are derived. Their metabolism is elevated, which allows them to sustain higher proliferative rate and resist some cell death signals. This phenomenon, known as the "Warburg effect", has become the focus of intensive efforts in the discovery of new therapeutic targets and new cancer drugs. Both glycolysis and glutaminolysis pathways are enhanced in cancer cells. While glycolysis is enhanced to satisfy the increasing energy demand of cancer cells, glutaminolysis is enhanced to provide biosynthetic precursors for cancer cells. It was recently discovered that there is a tyrosine phosphorylation of a specific isoform of pyruvate kinase, the M2 isoform, that is preferentially expressed in all cancer cells, which results in the generation of pyruvate through a unique enzymatic mechanism that is uncoupled from ATP production. Pyruvate produced through this unique enzymatic mechanism is converted primarily into lactic acid, rather than acetyl-CoA for the synthesis of citrate, which would normally then enter the citric acid cycle. Inhibition of key enzymes in glycolysis and glutaminolysis pathways with small molecules has provided a novel but emerging area of cancer research and has been proven effective in slowing the proliferation of cancer cells, with several inhibitors being in clinical trials. This review paper will cover recent advances in the development of chemotherapeutic agents against several metabolic targets for cancer therapy, including glucose transporters, hexokinase, pyruvate kinase M2, glutaminase, and isocitrate dehydrogenase.

/pdf/inhibition-of-glycolysis-and-glutaminolysis-an-emerging-drug-3ec286m3q8.pdf

Inhibition of Glycolysis and Glutaminolysis: An Emerging Drug Discovery Approach to Combat Cancer.

Management of Unresected Stage III Non-small Cell Lung Cancer: A Systematic Review

Lonidamine (LND) is a compound originally developed as an infertility drug. By capitalizing on the unique energy requirements of many solid tumors including benign prostatic hyperplasia (BPH), LND has shown efficacy as an adjunct to either radiation or chemotherapy in the treatment of several advanced solid organ malignancies such as lung, breast, head and neck, and liver metastases. It has an excellent safety profile in over 20 years of use in Italy in thousands of cancer patients. Preliminary data suggest that it is safe and effective in the treatment of lower urinary tract symptoms associated with BPH by metabolically targeting the unique dependency of the prostate on energy production by glycolysis instead of the aerobe Krebs cycle. The observed effects include a fast reduction in serum prostate-specific antigen and prostate volume, and simultaneous improvements in symptoms and urinary flow rate. The fact that prostate cancer and high-grade prostatic intraepithelial neoplasia have similar metabolic circumstances suggests that LND might also be effective in various stages of the prostate cancer carcinogenesis.

The development of lonidamine for benign prostatic hyperplasia and other indications.

A randomised trial of MACC chemotherapy with or without lonidamine in advanced non-small cell lung cancer

Background. Combination chemotherapy with conventional antiproliferative drugs is becoming the treatment of choice for patients with advanced non-small cell lung cancer (NSCLC), a good performance status, and no major clinical contraindications. Lonidamine (LND), a new drug with an innovative mechanism of action, might potentiate anticancer activity, without increasing toxicity. Methods. In a Phase I1 study, 46 patients with advanced NSCLC were assigned to receive chemotherapy with the methotrexate, doxorubicin (Adriamycin, Adria Laboratories, Columbus, OH), cyclophosphamide, and lomustine (MACC) regimen, as originally described, plus LND, 150 mg orally, three times per day. Treatment was continued until progression of disease, occurrence of unacceptable toxic effects, or refusal by the patient (the median duration of MACC treatment was 6 weeks: 7 weeks for LND). Resuits. For the whole group of patients, actual dose intensities (DI) of MACC and LND were 95% and 67% of those projected (median values), respectively. There was a negative correlation between duration of chemotherapy and the DI of MACC reached in each patient. On the contrary, there was no correlation between the duration of treatment with LND and its DI. The DI of LND and MACC were not correlated with each other. In all, seven objective responses (only partial responses) were observed. The overall median survival time was 42 weeks (confidence limits [CL], 20-52). The median survival length of patients receiving the full dose of LND (450 mg daily for at least 1 week) was 46 weeks (CL, 28-67), as compared with the median survival of 19 weeks (lower

A phase II study of methotrexate, doxorubicin, cyclophosphamide, and lomustine chemotherapy and lonidamine in advanced non-small cell lung cancer.

Chemotherapy/radiation therapy plus/minus lonidamine in the treatment of non-small cell lung cancer (limited disease): preliminary results.

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Chemotherapy/radiation therapy plus/minus lonidamine in the treatment of non-small cell lung cancer (limited disease): preliminary results.