Oxamic acid analogues as LDH-C4-specific competitive inhibitors

Rodrı́guez-Páez, Lorena; Chena-Taboada, Miguel Angel; Cabrera-Hernández, Arturo; Cordero-Martínez, Joaquín; Wong, Carlos

doi:10.3109/14756366.2011.566221

Cited by 22 publications

(31 citation statements)

References 35 publications

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“…That is, the prodrugs impair sperm motility, causing antifertility effects. In previous reports by us and by others, we showed that inhibitors of LDH, diminished ATP levels and motility in mouse and human sperm [Hereng et al 2011;Rodríguez-Páez et al 2002;Rodríguez-Páez et al 2011]. On one hand, the results of this study showed that NBOXet is better than sodium oxamate, a nonspecific inhibitor of LDH isozymes, because 40 mM sodium oxamate inhibited normal motility of human spermatozoa by 31% when incubated in capacitating conditions for 120 min [Hereng et al 2011].…”

Section: Concentration (Mm)supporting

confidence: 50%

“…Effect of N-alkyl oxamate prodrugs on the mice sperm viability after 30 min incubation. mice testes [Rodríguez-Páez et al 2011]. Unexpectedly mouse sperm LDH-C4 was inhibited by NBOX to a greater extent than the mouse testes LDH-C4.…”

Section: Discussionmentioning

confidence: 83%

“…In previous studies we showed that N-alkyl oxamate derivatives are competitive inhibitors of LDH isozymes. Mice testes LDH-C4 was more sensitive than LDH-A4 and LDH-B4 to inhibition by oxamate derivatives, and were selective inhibitors of LDH-C4, compared with other non-glycolytic mouse dehydrogenases [Rodríguez-Páez et al 2011;Wong et al 1997].…”

Section: Discussionmentioning

confidence: 89%

“…It is possible that this result is influenced by the inhibition of the LDH-A4 isoenzyme present in mouse sperm since LDH-A4 was recently found in the principal piece of the flagellum [Odet et al 2011]. Lactate dehydrogenase-A4 from mouse skeletal muscle was inhibited by NBOX although 12 times less than LDH-C4 [Rodríguez-Páez et al 2011]. Hexoquinase and GAPDS sperm-specific glycolytic enzymes, were used as controls and were inhibited by the three oxamate derivatives.…”

Section: Discussionmentioning

confidence: 99%

“…In previous studies, we reported that oxamate analogues have potential for use in contraception because N-isopropyl and propyl oxamates were selective inhibitors of LDH-C4 from testes [Rodríguez-Páez et al 2011;Wong et al 1997]. Furthermore, N-propyl oxamate (NPOX) significantly reduced ATP levels and capacitation of mouse sperm.…”

Section: Introductionmentioning

confidence: 99%

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Effect of oxamic analogues on functional mice sperm parameters

Cordero-Martínez

Aguirre-Alvarado

Wong

et al. 2014

Systems Biology in Reproductive Medicine

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The present study evaluates the effect of oxamate derivatives (N-ethyl, N-propyl, N-butyl oxamates) on functional murine sperm parameters, towards a new male non-hormonal contraceptive. These derivatives are selective inhibitors of lactate dehydrogenase-C4 (LDH-C4). LDH-C4 is a sperm-specific enzyme that plays an important role in ATP production for maintaining progressive motility as well as to induce capacitation and hyperactivation. The results demonstrate that all oxamate derivatives selectively inhibited LDH-C4 in mouse sperm extracts. The IC 50 values for hexokinase and glyceraldehyde-3-phosphate dehydrogenase were at least an order of magnitude greater than LDH-C4 IC 50 values. Prodrugs of oxamate derivatives assayed on sperm cells diminished normal sperm motility parameters, acrosome reaction, and cell viability in a concentration dependent manner. Also, we performed in vivo studies to determine the potential toxicity and possible contraceptive ability of these inhibitors. Mouse sperm were more sensitive to the N-butyl oxamate ethyl ester (NBOXet). Furthermore, results showed that NBOXet was of a low toxicity substance that diminished the total and progressive motility as well as the kinematic parameters of sperm cells. Data from in vitro and in vivo studies showed that N-butyl oxamate and its prodrug, are selective inhibitors of sperm LDH-C4, has low toxicity, and inhibits sperm progressive motility, offering some of the desirable characteristics of a male contraceptive: effect, low toxicity, and selectivity.

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Section: Concentration (Mm)supporting

confidence: 50%

Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Effect of oxamic analogues on functional mice sperm parameters

Cordero-Martínez

Aguirre-Alvarado

Wong

et al. 2014

Systems Biology in Reproductive Medicine

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Targeting of lactate dehydrogenase C dysregulates the cell cycle and sensitizes breast cancer cells to DNA damage response targeted therapy

Belič

Decock

2021

Molecular Oncology

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The cancer testis antigen (CTA) lactate dehydrogenase C (LDHC) is a promising anti-cancer target with tumor-specific expression and immunogenicity. Interrogation of breast cancer patient cohorts from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) indicate that upregulation of LDHC expression correlates with unfavorable prognosis. Although the role of LDHC is well characterized in spermatocytes, its role in tumors remains largely unknown. We investigated whether LDHC is involved in regulating genomic stability and whether it could be targeted to affect tumor cellular fitness. Silencing LDHC in four breast cancer cell lines significantly increased the presence of giant cells, nuclear aberrations, DNA damage and apoptosis. LDHC-silenced cells demonstrated aberrant cell cycle progression with differential expression of cell cycle checkpoint and DNA damage response regulators. In addition, LDHC silencing induced microtubule destabilization, culminating in increased mitotic catastrophe and reduced long-term survival. Notably, the clonogenicity of LDHC-silenced cells was further reduced by treatment with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib, and with the DNA-damaging drug cisplatin. This study supports the therapeutic potential of targeting LDHC to mitigate cancer cell survival, and improve sensitivity to agents that cause DNA damage or inhibit its repair.

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Characterization and Inhibitor Screening of Plateau Zokor Lactate Dehydrogenase C4

Zhang

Huang

et al. 2016

Appl Biochem Biotechnol

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Lactate dehydrogenase C4 (LDH-C4) is considered to be a target protein for the development of contraceptives. In this work, the characterization of plateau zokor LDH-C4 and the screening of a series of N-substituted oxamic acids as inhibitors against zokor LDH-C4 were reported. The cDNA of zokor LDH-C gene was cloned and expressed in Escherichia coli, from which the protein was purified and further characterized. The protein was a tetramer (LDH-C4) and thermally stable up to 62 °C with a K m of 63.9 μM for pyruvate and with optimal pH values of 7.95 and 10.1 for the forward and backward reactions respectively. Virtual and in vitro screening against zokor LDH-C4 revealed eight N-substituted oxamic acids with IC50s ranging from 198 to 2513 μM, higher than that of oxamic acid (150 μM) and (ethylamino)(oxo)acetic acid (59 μM). The inhibition potencies of N-substituted oxamic acids tested are in the micromolar range, and the increase in the length of substituting chain seems not to increase inhibition potency.

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Oxamic acid analogues as LDH-C4-specific competitive inhibitors

Cited by 22 publications

References 35 publications

Effect of oxamic analogues on functional mice sperm parameters

Effect of oxamic analogues on functional mice sperm parameters

Targeting of lactate dehydrogenase C dysregulates the cell cycle and sensitizes breast cancer cells to DNA damage response targeted therapy

Characterization and Inhibitor Screening of Plateau Zokor Lactate Dehydrogenase C4

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