Epidoxorubicin and lonidamine in refractory or recurrent epithelial ovarian cancer

Gadducci, Angiolo; Brunetti, I.; Muttini, M. P.; Fanucchi, A; Dargenio, F.; Giannessi, Pier Giorgio; Conte, Pierfranco

doi:10.1016/0959-8049(94)00231-s

Cited by 28 publications

(8 citation statements)

References 18 publications

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“…On the one hand, glucose transport inhibitors, such as silybin/silibinin [tested in a phase I/II clinical trials for prostate cancer and advanced hepatocellular carcinoma (Flaig et al, 2006)], phloretin, WZB117 and fasentin caused important side effects, since GLUT transporters are present in all the cells of the organism. Similarly, inhibition of glycolytic enzymes, such as hexokinase II with lonidamine, has been tested in several types of cancers, including breast, lung and ovarian cancer (Gadducci et al, 1994; De Lena et al, 1997; De Marinis et al, 1999; Berruti et al, 2002). However, there was no significant improvement in overall survival and many cases presented with elevated toxicity.…”

Section: Therapeutic Targeting Of Cscs Metabolismmentioning

confidence: 99%

Metabolism-Based Therapeutic Strategies Targeting Cancer Stem Cells

et al. 2019

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Cancer heterogeneity constitutes the major source of disease progression and therapy failure. Tumors comprise functionally diverse subpopulations, with cancer stem cells (CSCs) as the source of this heterogeneity. Since these cells bear in vivo tumorigenicity and metastatic potential, survive chemotherapy and drive relapse, its elimination may be the only way to achieve long-term survival in patients. Thanks to the great advances in the field over the last few years, we know now that cellular metabolism and stemness are highly intertwined in normal development and cancer. Indeed, CSCs show distinct metabolic features as compared with their more differentiated progenies, though their dominant metabolic phenotype varies across tumor entities, patients and even subclones within a tumor. Following initial works focused on glucose metabolism, current studies have unveiled particularities of CSC metabolism in terms of redox state, lipid metabolism and use of alternative fuels, such as amino acids or ketone bodies. In this review, we describe the different metabolic phenotypes attributed to CSCs with special focus on metabolism-based therapeutic strategies tested in preclinical and clinical settings.

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Section: Therapeutic Targeting Of Cscs Metabolismmentioning

confidence: 99%

Metabolism-Based Therapeutic Strategies Targeting Cancer Stem Cells

et al. 2019

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“…LND pharmacokinetic studies have been investigated in advanced breast cancer (68) and lung cancer patients (69) as part of phase II evaluation of the LND with wide variation in plasma concentration. Detailed Phase II clinical trials of LND have been performed in patients with breast cancer (70–73), lung cancer (74–76), ovarian cancer (77–80), and head neck cancer (81–83). Phase III clinical trials have also been performed on metastatic breast cancer (84–88) and lung cancer (89–93) patients.…”

Section: Lonidamine (Lnd) Toxicitymentioning

confidence: 99%

Mechanism of antineoplastic activity of lonidamine

Nath

Guo

Nancolas

et al. 2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

126

137

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Lonidamine (LND) was initially introduced as an antispermatogenic agent. It was later found to have anticancer activity sensitizing tumors to chemo-, radio-, photodynamic-therapy and hyperthermia. Although the mechanism of action remained unclear, LND treatment has been known to target metabolic pathways in cancer cells. It has been reported to alter the bioenergetics of tumor cells by inhibiting glycolysis and mitochondrial respiration, while indirect evidence suggested that it also inhibited L-lactic acid efflux from cells mediated by members of the proton-linked monocarboxylate transporter (MCT) family and also pyruvate uptake into the mitochondria by the mitochondrial pyruvate carrier (MPC). Recent studies have demonstrated that LND potently inhibits MPC activity in isolated rat liver mitochondria (Ki 2.5 μM) and cooperatively inhibits L-lactate transport by MCT1, MCT2 and MCT4 expressed in Xenopus laevis oocytes with K0.5 and Hill Coefficient values of 36–40 μM and 1.65–1.85, respectively. In rat heart mitochondria LND inhibited the MPC with similar potency and uncoupled oxidation of pyruvate was inhibited more effectively (IC50 ~7 μM) than other substrates including glutamate (IC50 ~20 μM). LND inhibits the succinate-ubiquinone reductase activity of respiratory Complex II without fully blocking succinate dehydrogenase activity. LND also induces cellular reactive oxygen species through Complex II and has been reported to promote cell death by suppression of the pentose phosphate pathway, which resulted in inhibition of NADPH and glutathione generation. We conclude that MPC inhibition is the most sensitive anti-tumour target for LND, with additional inhibitory effects on MCT-mediated L-lactic acid efflux, Complex II and glutamine/glutamate oxidation.

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“…In another clinical study, lonidamine (LND), which inhibits aerobic glycolytic activity by influencing HK2 (23), was used with high dose epidoxorubicin for refractory epithelial ovarian cancer. The results indicated that this therapeutic strategy had an excellent second-line therapeutic activity for patients (23). Furthermore, the addition of LND to the carboplatin/cisplatin-paclitaxel standard regimen for advanced ovarian cancer was demonstrated to overcome cisplatin resistance in patients (24).…”

Section: Glycolysis-related Enzymes Contribute To Chemotherapy Resistance In Cancer Cellsmentioning

confidence: 98%

Altered glycolysis results in drug‑resistant in clinical tumor therapy (Review)

Peng

Cui

et al. 2021

Oncol Lett

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Cancer cells undergo metabolic reprogramming, including increased glucose metabolism, fatty acid synthesis and glutamine metabolic rates. These enhancements to three major metabolic pathways are closely associated with glycolysis, which is considered the central component of cancer cell metabolism. Increasing evidence suggests that dysfunctional glycolysis is commonly associated with drug resistance in cancer treatment, and aberrant glycolysis plays a significant role in drug-resistant cancer cells. Studies on the development of drugs targeting these abnormalities have led to improvements in the efficacy of tumor treatment. The present review discusses the changes in glycolysis targets that cause drug resistance in cancer cells, including hexokinase, pyruvate kinase, pyruvate dehydrogenase complex, glucose transporters, and lactate, as well the underlying molecular mechanisms and corresponding novel therapeutic strategies. In addition, the association between increased oxidative phosphorylation and drug resistance is introduced, which is caused by metabolic plasticity. Given that aberrant glycolysis has been identified as a common metabolic feature of drug-resistant tumor cells, targeting glycolysis may be a novel strategy to develop new drugs to benefit patients with drug-resistance.

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Epidoxorubicin and lonidamine in refractory or recurrent epithelial ovarian cancer

Cited by 28 publications

References 18 publications

Metabolism-Based Therapeutic Strategies Targeting Cancer Stem Cells

Metabolism-Based Therapeutic Strategies Targeting Cancer Stem Cells

Mechanism of antineoplastic activity of lonidamine

Altered glycolysis results in drug‑resistant in clinical tumor therapy (Review)

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