Xylochemical Synthesis and Biological Evaluation of the Orchidaceous Natural Products Isoarundinin I, Bleochrin F, Blestanol K, and Pleionol

Geske, Leander; Baier, Joris; Boulos, Joelle C.; Efferth, Thomas; Opatz, Till

doi:10.1021/acs.jnatprod.2c00830

Cited by 1 publication

(2 citation statements)

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“…According to our findings, CEM/ADR5000 cells and their sensitive counterparts both demonstrated a similar level of sensitivity to adapalene. Furthermore, the resistance ratio was just 1.26, which is far lower than that of doxorubicin, a common chemotherapeutic medication with a cross-resistance ratio much more than 1000 [ 30 ]. These findings suggested that adapalene is not involved in the cross-resistance profile conferred by P-glycoprotein.…”

Section: Discussionmentioning

confidence: 99%

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In Silico, In Vitro, and In Vivo Investigations on Adapalene as Repurposed Third Generation Retinoid against Multiple Myeloma and Leukemia

Boulos,

Chatterjee,

Shan

et al. 2023

Cancers

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The majority of hematopoietic cancers in adults are incurable and exhibit unpredictable remitting-relapsing patterns in response to various therapies. The proto-oncogene c-MYC has been associated with tumorigenesis, especially in hematological neoplasms. Therefore, targeting c-MYC is crucial to find effective, novel treatments for blood malignancies. To date, there are no clinically approved c-MYC inhibitors. In this study, we virtually screened 1578 Food and Drug Administration (FDA)-approved drugs from the ZINC15 database against c-MYC. The top 117 compounds from PyRx-based screening with the best binding affinities to c-MYC were subjected to molecular docking studies with AutoDock 4.2.6. Retinoids consist of synthetic and natural vitamin A derivatives. All-trans-retinoic acid (ATRA) were highly effective in hematological malignancies. In this study, adapalene, a third-generation retinoid usually used to treat acne vulgaris, was selected as a potent c-MYC inhibitor as it robustly bound to c-MYC with a lowest binding energy (LBE) of −7.27 kcal/mol, a predicted inhibition constant (pKi) of 4.69 µM, and a dissociation constant (Kd value) of 3.05 µM. Thus, we examined its impact on multiple myeloma (MM) cells in vitro and evaluated its efficiency in vivo using a xenograft tumor zebrafish model. We demonstrated that adapalene exerted substantial cytotoxicity against a panel of nine MM and two leukemic cell lines, with AMO1 cells being the most susceptible one (IC50 = 1.76 ± 0.39 µM) and, hence, the focus of this work. Adapalene (0.5 × IC50, 1 × IC50, 2 × IC50) decreased c-MYC expression and transcriptional activity in AMO1 cells in a dose-dependent manner. An examination of the cell cycle revealed that adapalene halted the cells in the G2/M phase and increased the portion of cells in the sub-G0/G1 phase after 48 and 72 h, indicating that cells failed to initiate mitosis, and consequently, cell death was triggered. Adapalene also increased the number of p-H3(Ser10) positive AMO1 cells, which is a further proof of its ability to prevent mitotic exit. Confocal imaging demonstrated that adapalene destroyed the tubulin network of U2OS cells stably transfected with a cDNA coding for α-tubulin-GFP, refraining the migration of malignant cells. Furthermore, adapalene induced DNA damage in AMO1 cells. It also induced apoptosis and autophagy, as demonstrated by flow cytometry and western blotting. Finally, adapalene impeded tumor growth in a xenograft tumor zebrafish model. In summary, the discovery of the vitamin A derivative adapalene as a c-MYC inhibitor reveals its potential as an avant-garde treatment for MM.

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Section: Discussionmentioning

confidence: 99%

“…The sensitivity of MM cells, leukemia cells, and PBMCs to adapalene was evaluated by the resazurin reduction assay, as previously described [ 30 ]. In brief, 10 4 cells were seeded in each well of a flat bottom 96-well plate.…”

Section: Methodsmentioning

confidence: 99%