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  • Flavonoids protein interactions studies play a substantial p

    2023-01-24

    Flavonoids-protein interactions studies play a substantial part in the hunt for novel molecules which are to interact with a selected disease-relevant target [35]. The mode of potential interaction gives information about the flavonoid effectiveness and selectivity. Lately, possible target molecules and not the mode of interaction with targets constituents has been an important focus of current pharmacological research of kolaviron bioflavonoids complex [36], [37], [38], [39]. Here, the KB-R7943 mesylate mode of this potential drug candidate interaction with target/carrier protein was sought. We report the binding interaction of kolaviron–kolaflavanone with ALDH by multiple spectroscopic methods under physiological conditions and molecular modeling to understanding the thermodynamics of its interaction in vivo.
    Materials and methods
    Results and discussion
    Conclusions
    Acknowledgments This work was partly supported by the FUTA TETFund Research grant. AOK thanks IFS for the funds (F/4449 1F and F/4449-2F) used to purchase the equipments.
    Introduction Aldehyde dehydrogenases (ALDHs) are a group of enzymes that metabolize endogenous and exogenous aldehydes to their corresponding carboxylic acids. ALDH activity is crucial for cell differentiation [1], detoxification [2] and drug resistance [3,4]. Recently, high ALDH activity has also been shown in cancer stem KB-R7943 mesylate (CSCs) of different tumor types. Specifically, members of the ALDH1 subfamily appear to be directly involved in the therapy resistance phenotype of this particular subpopulation of tumor cells. It has been shown in several types of cancer cell lines including sarcoma [5], breast [6], lung [7] and gastric [8] cancer, that ALDH1high cells demonstrated higher resistance to common chemotherapeutic reagents than ALDH1low cells. In addition, we confirmed ALDH1 as a new mediator of chemoresistance in glioblastoma and a predictor of clinical outcome [9]. Of the 19 ALDH isoforms, ALDH1A3 expression is important for maintaining non-small cell lung cancer stem cells [10] and is associated with a worse prognosis of patients suffering from high grade glioma [11]. ALDH1A3 has also been indicated as a marker of the mesenchymal phenotype in glioblastomas [12,13]. However, the exact molecular mechanisms of which ALDH1 enzymes contribute to chemoresistance in human glioblastoma are within the limit of understanding. In recent years, the role of autophagy in tumor cell biology has attracted scientific interest. Autophagy is a survival-promoting process that contributes to the clearance of damaged proteins and organelles to maintain cellular homeostasis and genomic integrity [14]. However, the role of autophagy in cancer is still elusive, it has been reported either as tumor suppressor or promotor. Some studies confirm that the suppression of autophagy promotes certain cancer cell growth [[15], [16], [17], [18]]. On the other hand, in some cases, metabolic stress triggers autophagy, which serves as a back-up energy to enhance adaptation of cancer cells [[19], [20], [21]]. Interestingly, it has been shown that autophagy inhibition enhanced efficacy of chemotherapeutics in ALDHhigh breast cancer cells [22]. The antibiotic agent salinomycin (Sal) more efficiently inhibited autophagy in ALDHhigh breast cancer cells when compared with ALDHlow cells [23]. However, the enigmatic correlation between ALDH and autophagy in chemoresistance has not been investigated so far.
    Materials and methods
    Results
    Discussion In human glioblastoma, ALDH1 has been identified in the most resistant subpopulations of glial tumor cells, indicating that ALDH1 contributes to the development of the therapy resistance phenotype [6], [7], [8], [9],11,28,29]11,28,29]. The molecular pathway and ALDH1 isotypes that are involved in these processes are not characterized so far. In the present study, aldefluor activity was significantly downregulated in ALDH1A3 KO cells indicating that ALDH1A3 is a major regulator of ALDH enzyme activity in GBM cell lines. Our results are corroborated by the data of Paola et al. in breast cancer [6]. They show that among all ALDH isoforms, only ALDH1A3 knockdown leads to significant reduction of ALDH activity in breast cancer cells. ALDH1A3 is expressed in the majority of human cancers, and in almost half of gliomas. In a clinical study, Yang et al. suggested high ALDH1A3 expression associated with poor prognosis of gallbladder cancer [30]. In brain tumor patients Zhang et al. found higher expression of ALDH1A3 in high grade tumors when compared with low grade gliomas. They also observed higher mortality in patients suffering from ALDH1A3 overexpressing tumors [11]. Moreover, the oxidative ability of ALDH1A3 for all-trans retinal may be 10-fold higher than that of ALDH1A1 [31,32].