Effect of Tumor Relevant Acidic Environment in the Interaction of a N-hydroxyindole-2-Carboxylic Derivative with the Phospholipid Bilayer
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The inhibitors of the human isoform 5 of lactate dehydrogenase (hLDH5) have attracted growing interest as efficient anti-cancer agents. In the present paper, the interactions between an efficient hLDH5 inhibitor (N-hydroxyindole-2-carboxylic derivative) and lipid bilayers based on dipalmitoylphosphatidylcholine (DPPC) were investigated. Additionally, since interstitial acidification plays a key role in tumor pathogenesis and tumor drug therapy, the effect of acidic pH was assessed and correlated to DPPC/drug interaction.
Four different techniques were used: differential scanning calorimetry, dynamic light scattering, UV-VIS second derivative spectrometry and attenuated total reflection Fourier transformed infrared spectroscopy.
All techniques concur in highlighting a structural change of lipid assembly, susceptible both to pH change and to the presence of the antitumor compound. Lipid vesicles appeared more compact at the lower pH, since the thermal pre-transition from the lamellar gel phase to the ripple gel phase was absent at pH 7.4 and the infrared analysis revealed a stronger acyl chain packing as well as a different hydration degree. Drug interaction was mainly detected in the lipid region including the ester linkages and the first portion of the acyl chains. Furthermore, a lower drug partitioning was recorded at pH 6.6.
The investigated antitumor agent possesses a stable negative charge at the investigated pH values, thus the lower interaction at the acidic pH is mainly ascribable to an environmental effect on lipid assembly. Therefore, drug efficacy under tumor acid conditions may be hampered by the observed lipid membrane constraints, and suggest for the development of suitable prodrugs.
KEY WORDSDipalmitoylphosphatidylcholine (DPPC) hLDH5 inhibitor N-hydroxyindole derivatives tumor acidic pH
Attenuated total reflection Fourier transformed infrared spectroscopy
Dynamic light scattering
Differential scanning calorimetry
Human isoform 5 of lactate dehydrogenase
Acknowledgments and Disclosures
The research project was supported by Progetti di ricerca di Ateneo PRA 2017 of the University of Pisa.
- 2.Kolosenko I, Avnet S, Baldini N, Viklund J, De Milito A. Therapeutic implications of tumor interstitial acidification. Semin Cancer Biol. 2017;43:119–33. https://doi.org/10.1016/j.semcancer.2017.01.008.
- 4.Do TTT, Dao UPN, Bui HT, Nguyen TT. Effect of electrostatic interaction between fluoxetine and lipid membranes on the partitioning of fluoxetine investigated using second derivative spectrophotometry and FTIR. Chem Phys Lipids 2017;207(Pt A):10–23. doi: https://doi.org/10.1016/j.chemphyslip.2017.07.001.
- 6.Granchi C, Roy S, Giacomelli C, Macchia M, Tuccinardi T, Martinelli A, et al. Discovery of N-hydroxyindole-based inhibitors of human lactate dehydrogenase isoform A (LDH-A) as starvation agents against cancer cells. J Med Chem. 2011;54(6):1599–612. https://doi.org/10.1021/jm101007q.CrossRefPubMedGoogle Scholar
- 7.Granchi C, Calvaresi EC, Tuccinardi T, Paterni I, Macchia M, Martinelli A, et al. Assessing the differential action on cancer cells of LDH-A inhibitors based on the N-hydroxyindole-2-carboxylate (NHI) and malonic (Mal) scaffolds. Org Biomol Chem. 2013;11(38):6588–96. https://doi.org/10.1039/c3ob40870a.CrossRefPubMedGoogle Scholar
- 16.Mantsch HH, Chapman D, editors. Infrared spectroscopy of biomolecules. New York: Wiley-Liss; 1996.Google Scholar
- 25.Smith EA, Dea PK. Differential scanning calorimetry studies of phospholipid membranes: the interdigitated gel phase. In: Elkordy AA, editor. Applications of calorimetry in a wide context-differential scanning calorimetry, isothermal titration calorimetry and microcalorimetry. Rijeka: InTech; 2013. p. Ch. 18.Google Scholar
- 27.Cinelli S, Onori G, Zuzzi S, Bordi F, Cametti C, Sennato S, et al. Properties of mixed DOTAP-DPPC bilayer membranes as reported by differential scanning calorimetry and dynamic light scattering measurements. J Phys Chem B. 2007;111(33):10032–9. https://doi.org/10.1021/jp071722g.CrossRefPubMedGoogle Scholar
- 30.Briuglia ML, Rotella C, McFarlane A, Lamprou DA. Influence of cholesterol on liposome stability and on in vitro drug release. Drug Deliv Transl Res. 2015;5:231.Google Scholar
- 32.Tan LT-H, Chan K-G, Pusparajah P, et al. Targeting membrane lipid a potential Cancer cure? Front Pharmacol. 2017;8:12.Google Scholar