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Does affinity of Cisplatin to B-Vitamins impair the therapeutic effect in the case of patient with lung cancer consuming carrot or beet juice?

Beata Szefler,Przemysław Czeleń,A. Szczepanik,P. Cysewski

Published 2019 in Anti-Cancer Agents in Medicinal Chemistry

ABSTRACT

BACKGROUND Cisplatin (CisPt) has a well-recognized anticancer activity by interacting with DNA and inducing programmed cell death. However, theoretical studies performed on the molecular level suggest that such nonspecific interactions can also take place with many competitive compounds, such as vitamins containing aromatic rings with lone-pair orbitals. It is argued that such direct analogy to interaction of canonical purines can impair the therapeutic effect of Cisplatin. This might be an indicator of reduction of the anticancer therapeutic effects of Cisplatin drug in the presence of vitamins inside the cell nucleus. Based on this observation, the regular intake of vitamin-rich beet root or carrot juices is strongly discouraged during anticancer therapy using CisPt drug and detailed clinical trials seem to be indispensable. All obtained computational, experimental and clinical results will be the basis for improvement of targeted anti-cancer therapy using Cisplatin and its derivatives. OBJECTIVE The aim of this work is a theoretical study on the initial Pt-N7(N1) bond formation with vitamins from B group and their comparison with values characterizing native purines. The performed tests and the obtained results will be the basis for experimental studies and detailed clinical trials seem to be indispensable. Method Geometries of studied structures were optimized with an aid of Gaussian 09[1] using the B3LYP functional with the 6-31G** basis set. Atomic orbitals of Platinum were represented by the lanl2dz basis set including relativistic effective core potentials needed in the case of heavy atoms. Vibrational frequency calculations at the B3LYP/ 6-31G** level of theory were used to derive the zero-point-energy (ZPE) and vibrational entropy corrections at room temperature at the same level of theory. Solvation free energies were evaluated by a self-consistent reaction field (SCRF) approach based on accurate numerical solutions of the Poisson-Boltzmann equation using the gas-phase geometries. A dielectric constant of 78 for water was used in the PCM continuum model computations along with radii Bondii. The chemical affinity was computed by adding contributions of ZPE corrections, thermal corrections to the enthalpy, entropy terms, and continuum solvation free energies. RESULTS The affinities of B-vitamins to cisPt were quantified and compared to interactions with canonical purines. Particularly, the affinities of mono-aqua cis~[Pt(NH3)2Cl(H2O)]+ and di-aqua cis~ [Pt(NH3)2(H2O)2]2+ derivatives of Cisplatinum toward compounds belonging to the group of eight B vitamins were studied. All of them contain nitrogen atoms with lone electron pairs in their structure, which allow for formation of adducts analogous to the ones of cisPt with purines. For all considered compounds, the computed values of Gibbs Free Energies of reaction (ΔGr) indicate a spontaneous complexation process. However, a high diversity in reactivity of particular vitamins was noticed. It has been found that for all of the studied chloroaqua and diaqua Platinum complexes, the estimated values of Gibbs free energy of reaction ΔGr are negative. Based on these values, it is concluded that the reactivities of mono cis~[Pt(NH3)2Cl(H2O)]+ - niacin (B3) and di-aqua cis~ [Pt(NH3)2(H2O)2]2+ - niacin (B3) are supposed to be the strongest among all studied vitamins, as for all considered reactions the highest Gibbs free energy values were obtained in these cases. Another vitamin, namely thiamine (B1), contains two nitrogen atoms (N1, N7) which could act as two possible points of addition of Cisplatinum molecule. Obtained data clearly shows that creation of complexes with cisPt monomers connected with nitrogen N1 is more preferable in the case of both reaction models. Similar reactivity as Thiamine is also shown by Pyridoxal phosphate (B6) and in this case the highest differences between values obtained for complexes created with mono and cisPt-diaqua molecules are observed. The possibility of the occurrence of internal hydrogen bonds created by water molecule with oxygen from phosphate group caused the decreasing of ΔGr relative to mono aqua complex by ~ 9 kcal/mol. The smallest reactivity among all considered vitamins is shown by riboflavin (B2), as in the case of both possible types of complexes ΔGr values are relatively low compared to the other considered compounds. All values of ΔGr unambiguously indicate that reactions with cisPt-diaqua are more preferable, but the comparison of ΔGr values obtained for compounds from vitamin B group and the ones characterizing complexes created by Guanine molecules indicates higher affinity of cisPt monomers towards purines. The differences are particularly noticeable in the case of reactions with cisPt-diaqua while in the case of mono aqua derivatives similar values of affinities can be found, as in the case of niacin (B3). CONCLUSION Based on these observations, the regular intake of vitamin-rich beet root or carrot juices is strongly discouraged during anticancer therapy using CisPt drug. On the other hand, considering the pharmacokinetics of cisplatin and its high nephro-, neuro- and ototoxicity, administration of preparations containing vitamin B6 after the infusion of Cisplatin seems to be appropriate. In clinical conditions, the administration of this vitamin takes place in the preparation containing magnesium ions and vit. B6, between subsequent infusions of the anticancer drug. Patient receives small daily doses of vitamin B6 (2.5 mg per day) as this compound increases the bioavailability of magnesium ions, which in turn causes a reduction of the toxic effect of cisPt during anticancer treatment, specifically reduction of the neuropathic effect. Thus, on one hand, magnesium ions will have a clinically planned role to reduce the undesired effects of an anticancer drug while on the other hand vitamin B6 will form complexes with residues of Cisplatin in the body, what could also reduce its toxicity. In order to confirm the results of the performed computational study, detailed clinical trials should be performed.

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