Analytical aspects of sunitinib and its geometric isomerism towards therapeutic drug monitoring in clinical routine

Posocco, Bianca; Buzzo, Mauro; Giodini, Luciana; Crotti, Sara; DaRonco, S.; Traldi, Pietro; Agostini, Marco; Marangon, Elena; Toffoli, Giuseppe

doi:10.1016/j.jpba.2018.08.013

Cited by 25 publications

(14 citation statements)

References 27 publications

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“…Sunitinib and its active metabolite ( N -desethyl sunitinib) are prone to spontaneous isomerization induced through light exposure. Two stereoisomeric forms are known and have been detected in our study ( Figure 4 ), the E (trans) and Z (cis) isomer [ 31 , 32 , 33 ]. The isomerization limits the accurate quantification of both stereoisomeric forms in cellular extracts or the plasma of patients.…”

Section: Discussionmentioning

confidence: 67%

“…Diverse studies showed the presence of both stereoisomers, ( E )-sunitinib and ( Z )-sunitinib [ 23 , 31 , 33 ]. Attribution was made by comparing the retention times and stereoisomeric ratios with the literature [ 32 ] and a standard solution in methanol ( Supplementary Figure S8A ). ( E )-sunitinib ( Figure 4 A, 1) appears to be clinically inactive, and its isomerization occurs through light exposure [ 31 , 33 ].…”

Section: Resultsmentioning

confidence: 99%

“…Evaluating the anti-cancer efficacy, as well as the pharmacokinetics of sunitinib and its active metabolite ( N -desethyl sunitinib), demonstrated high interpatient variability [ 31 ], potentially linked to the light-dependent isomerism of sunitinib [ 31 , 32 ]. The reversible isomerization from the ( Z )- to the ( E )-isomer occurs through light exposure, independent of the dose [ 31 , 32 , 33 ]. How isomerization and metabolism link to sunitinib resistance is not yet fully understood.…”

Section: Introductionmentioning

confidence: 99%

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Molecular and Functional Analysis of Sunitinib-Resistance Induction in Human Renal Cell Carcinoma Cells

Rausch

Rutz

Allard

et al. 2021

IJMS

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Resistance in clear cell renal cell carcinoma (ccRCC) against sunitinib is a multifaceted process encompassing numerous molecular aberrations. This induces clinical complications, reducing the treatment success. Understanding these aberrations helps us to select an adapted treatment strategy that surpasses resistance mechanisms, reverting the treatment insensitivity. In this regard, we investigated the dominant mechanisms of resistance to sunitinib and validated an optimized multidrug combination to overcome this resistance. Human ccRCC cells were exposed to single or chronic treatment with sunitinib to obtain three resistant clones. Upon manifestation of sunitinib resistance, morphometric changes in the cells were observed. At the molecular level, the production of cell membrane and extracellular matrix components, chemotaxis, and cell cycle progression were dysregulated. Molecules enforcing the cell cycle progression, i.e., cyclin A, B1, and E, were upregulated. Mass spectrometry analysis revealed the intra- and extracellular presence of N-desethyl sunitinib, the active metabolite. Lysosomal sequestration of sunitinib was confirmed. After treatment with a synergistic optimized drug combination, the cell metabolic activity in Caki-1-sunitinib-resistant cells and 3D heterotypic co-cultures was reduced by >80%, remaining inactive in non-cancerous cells. These results demonstrate geno- and phenotypic changes in response to sunitinib treatment upon resistance induction. Mimicking resistance in the laboratory served as a platform to study drug responses.

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Section: Discussionmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular and Functional Analysis of Sunitinib-Resistance Induction in Human Renal Cell Carcinoma Cells

Rausch

Rutz

Allard

et al. 2021

IJMS

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“…Isomerism is one of the most common features that has been observed in many systems, including small molecules, biomolecules, and macroscopic world . With the deepening of the corresponding research, nanoparticle isomerism has become a promising field of study in nanoscience as it opens the possibility in chiral applications such as chiral catalysis and sensing .…”

Section: The Relative Energy (E In Unit Of Ev) Of the [Au4cu4(dppm)2mentioning

confidence: 99%

Isomer Structural Transformation in Au–Cu Alloy Nanoclusters: Water Ripple‐Like Transfer of Thiol Ligands

Xiong

et al. 2019

Part & Part Syst Charact

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Structure isomerism is observed in noble metal nanoclusters; however, the mechanism study of this process is rarely reported. Herein, by using the biphosphine ligands instead of phosphine ligands, the high symmetry of the Au2Cu6(PPh3)2(SAdm)6 nanocluster is successfully broken and [Au4Cu4(L1)2(SAdm)5]Br (where, L1 is bis(diphenylphosphine)methane, DPPM) nanocluster is obtained with chiral arrangement. This newly obtained nanocluster contains a total of four isomers in crystal unit cell. Interestingly, these isomers undergo rapid isomorphism in solution, which is confirmed by 1H‐1H COSY spectrum. Density functional theory calculations demonstrate that the water ripple–like transfer of the thiol ligands results from the isomorphism of nanoclusters.

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“…20 SUN has an exocyclic alkenyl group and is capable of showing Z-E isomerism (Scheme 1) due to the presence of a double bond between 2-oxindol and the pyrrole ring. 34,35 The Z isomer is the principal clinical form of the drug and it is stabilized by internal hydrogen bonds between the 2-oxindol and the pyrrole ring. The literature data 34 show that the Z-isomer is not stable in acidic media, because a high concentration of H + ions in the medium can interfere with the formation of internal hydrogen bonds, thus counteracting the thermodynamic stability of the Z-isomer and favoring the prevalence of the E-isomer.…”

Section: Cyclic Voltammetrymentioning

confidence: 99%

Voltammetric responses at modified electrodes and aggregation effects of two anticancer molecules: irinotecan and sunitinib

2020

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Analytical aspects of sunitinib and its geometric isomerism towards therapeutic drug monitoring in clinical routine

Cited by 25 publications

References 27 publications

Molecular and Functional Analysis of Sunitinib-Resistance Induction in Human Renal Cell Carcinoma Cells

Molecular and Functional Analysis of Sunitinib-Resistance Induction in Human Renal Cell Carcinoma Cells

Isomer Structural Transformation in Au–Cu Alloy Nanoclusters: Water Ripple‐Like Transfer of Thiol Ligands

Voltammetric responses at modified electrodes and aggregation effects of two anticancer molecules: irinotecan and sunitinib

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