The Configuration-Dependent Anti-Leukemic Effect of Manoalide Stereoisomers: Reignite Research Interest in these Sponge-Derived Sesterterpenoids

Lai, Kuei Hung; Peng, Bo; Hsu, Yu Ming; El-Shazly, Mohamed; Du, Ying; Lu, Mei; Su, Jui Hsin; Liu, Yi Chang

doi:10.1016/j.bioorg.2021.105150

Cited by 3 publications

(9 citation statements)

References 30 publications

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“…An approach to overcome these limitations could be the use of dual inhibitors. Multiple marine-derived compounds described in this review such as 25-acetals manoalide, xestoquinone, HA-A, and M7, inhibit both topo I and topo II [55,60,61,76], while for others, topo II inhibitory activity is accompanied by the inhibition of Hsp90 [36,62,74] or HDAC [75,76]. The resulting advantages are manifold.…”

Section: Discussionmentioning

confidence: 99%

“…All the derivates were tested on multiple leukemia cell lines (Table 1). The compounds L2, L4, M7, and M9, bearing a 24R, 25S configuration, were the most effective, thus assuming that the cytotoxic activity was configuration-dependent [61]. The administration of M7 to immunodeficient athymic mice (1 μg/kg every day for 33 days) reduced the tumor growth of Molt-4 xenograft by about 66%, without affecting body weight [61].…”

Section: Manoalide-like Sesterterpenoidsmentioning

confidence: 97%

“…M7 has been shown to act as a catalytic inhibitor of topo IIα. Moreover, it inhibited DNA relaxation with an IC50 value of 1.18 μM and promoted the formation of supercoiled DNA products in the presence of topo IIα [61]. Compared to manoalide 25-acetals, the inhibitory activity of M7 toward topo II was greatly higher, although purified topo II from two different organisms were used: human for M7 [61] and calf thymus for manoalide 25acetals [60].…”

Section: Manoalide-like Sesterterpenoidsmentioning

confidence: 99%

“…Moreover, it inhibited DNA relaxation with an IC50 value of 1.18 μM and promoted the formation of supercoiled DNA products in the presence of topo IIα [61]. Compared to manoalide 25-acetals, the inhibitory activity of M7 toward topo II was greatly higher, although purified topo II from two different organisms were used: human for M7 [61] and calf thymus for manoalide 25acetals [60]. The topo IIα catalytic inhibitor activity was associated with DNA damage, as demonstrated by its ability to promote the phosphorylation of ATM, Chk2, and H2A.X and to induce DNA DSBs at 0.75 μM in Molt-4 cells.…”

Section: Manoalide-like Sesterterpenoidsmentioning

confidence: 99%

“…The topo IIα catalytic inhibitor activity was associated with DNA damage, as demonstrated by its ability to promote the phosphorylation of ATM, Chk2, and H2A.X and to induce DNA DSBs at 0.75 μM in Molt-4 cells. M7-induced DNA damage has been found to activate apoptotic cell death, as indicated by and the activation of Casp-3, -8, and -9, the disruption of MMP, and the cleavage of PARP [61].…”

Section: Manoalide-like Sesterterpenoidsmentioning

confidence: 99%

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Marine-Derived Compounds Targeting Topoisomerase II in Cancer Cells: A Review

et al. 2022

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Cancer affects more than 19 million people and is the second leading cause of death in the world. One of the principal strategies used in cancer therapy is the inhibition of topoisomerase II, involved in the survival of cells. Side effects and adverse reactions limit the use of topoisomerase II inhibitors; hence, research is focused on discovering novel compounds that can inhibit topoisomerase II and have a safer toxicological profile. Marine organisms are a source of secondary metabolites with different pharmacological properties including anticancer activity. The objective of this review is to present and discuss the pharmacological potential of marine-derived compounds whose antitumor activity is mediated by topoisomerase II inhibition. Several compounds derived from sponges, fungi, bacteria, ascidians, and other marine sources have been demonstrated to inhibit topoisomerase II. However, some studies only report docking interactions, whereas others do not fully explain the mechanisms of topoisomerase II inhibition. Further in vitro and in vivo studies are needed, as well as a careful toxicological profile evaluation with a focus on cancer cell selectivity.

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Section: Discussionmentioning

confidence: 99%

Section: Manoalide-like Sesterterpenoidsmentioning

confidence: 97%

Section: Manoalide-like Sesterterpenoidsmentioning

confidence: 99%

Section: Manoalide-like Sesterterpenoidsmentioning

confidence: 99%

Section: Manoalide-like Sesterterpenoidsmentioning

confidence: 99%

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Marine-Derived Compounds Targeting Topoisomerase II in Cancer Cells: A Review

et al. 2022

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Marine natural products

et al. 2023

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Natural product manoalide promotes EGFR-TKI sensitivity of lung cancer cells by KRAS-ERK pathway and mitochondrial Ca2+ overload-induced ferroptosis

Liu

Zeng

et al. 2023

Front. Pharmacol.

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Background: Manoalide (MA), a proven natural inhibitor of PLA2 has anticancer effects, but its potential application and mechanism as an anticancer drug to promote EGFR-TKI sensitivity in lung cancer cells have not been studied.Methods: KRAS-mutated lung cancer cells and organoids, acquired osimertinib-resistant lung cancer cell lines HCC827OR, were used as EGFR-TKI-resistant models. CCK-8, clone formation, apoptosis assays, and calcein-AM staining were performed to investigate the inhibitory effects of MA in lung cancer cells and organoids. The flow cytometry or confocal microscope was used to detect lipid droplets, ROS, lipid peroxidation, mitochondria Ca2+, and iron content. The oxygen consumption rate (OCR) and fatty acid oxidation (FAO) were used to estimate the effect of MA on mitochondrial function.Results: MA inhibits the proliferation of KRAS-mutated lung cancer cells and organoids. In addition, MA induces ER stress in a ROS-dependent mechanism. The ROS induced by MA is mainly in mitochondrial and causes lipid peroxidation, thereby inhibiting mitochondrial FAO metabolism and promoting the accumulation of lipid droplets. MA also suppresses the KRAS-ERK pathway through ROS and promotes the sensitivity of KRAS-mutated lung cancer cells and organoids to osimertinib. Furthermore, MA induces ferroptosis by suppressing the NRF2-SLC7A11 axis and mitochondrial Ca2+ overload induced-FTH1 pathways to promote the sensitivity of osimertinib-resistant lung cancer cells to osimertinib.Conclusions: MA is a candidate EGFR-TKI sensitizer in KRAS-mutated and osimertinib-resistant lung cancer cells.

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The Configuration-Dependent Anti-Leukemic Effect of Manoalide Stereoisomers: Reignite Research Interest in these Sponge-Derived Sesterterpenoids

Cited by 3 publications

References 30 publications

Marine-Derived Compounds Targeting Topoisomerase II in Cancer Cells: A Review

Marine-Derived Compounds Targeting Topoisomerase II in Cancer Cells: A Review

Marine natural products

Natural product manoalide promotes EGFR-TKI sensitivity of lung cancer cells by KRAS-ERK pathway and mitochondrial Ca2+ overload-induced ferroptosis

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