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Bidesmosidic betulin saponin bearing L-rhamnopyranoside moieties induces apoptosis and inhibition of lung cancer cells growth in vitro and in vivo

Mihoub Mouadh, Pichette André, Sylla Balla, Gauthier Charles et Legault Jean. (2018). Bidesmosidic betulin saponin bearing L-rhamnopyranoside moieties induces apoptosis and inhibition of lung cancer cells growth in vitro and in vivo. PLOS ONE, 13, (3), e0193386.

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Betulin has a wide range of biological and pharmacological properties with its anticancer activity attracting most of the attention as it offers a possible alternative treatment to chemotherapy. However, betulin’s in vivo biological effectiveness is limited by its poor solubility. As such, we synthesized polar glycosylated derivatives to increase its hydrosolubility and enhance its pharmacological properties. Among these synthesized compounds, 28-O-α-l-rhamnopyranosylbetulin 3β-O-α-l-rhamnopyranoside (Bi-L-RhamBet) was assessed for its cytotoxic effects against a suite of lung cancer cell lines. We also investigated its mechanism of action using an A549 lung cancer cell line. Our results showed that Bi-L-RhamBet exhibited potent cytotoxic activity toward lung cancer cell lines including A549, NCI-H2087, NCI-H522, NCI-H1993 NCI-H1755, and LLC1 having IC50 values ranging from 2.9 to 5.9 μM. Moreover, Bi-L-RhamBet (50 mg/kg) significantly inhibited tumor growth with a treatment-to-control ratio (T/C) of 0.54 and a tumor growth inhibition rate of 46% at day 18 (p < 0.05). Microscopic observations of A549 cells, double stained with acridine orange and ethidium bromide, showed apoptotic features. Bi-L-RhamBet induced activation of pro-apoptotic caspases 8, 9, and 3/7 as well as causing DNA fragmentation. Moreover, a marked increase in mitochondrial ROS (mROS) was coupled with a reduction of mitochondrial potential. Interestingly, the presence of mitochondrial electron transport chain (ETC) inhibitors, including rotenone, malonate, and antimycin A, reduced mROS production, and the activation of caspases suggesting that Bi-L-RhamBet disturbs the ETC. Finally, dichloroacetate, a pyruvate dehydrogenase kinase inhibitor potentiated the cytotoxicity of Bi-L-RhamBet against A549 cells. Taken together, these data suggest that Bi-L-RhamBet can induce apoptotic cell death via disturbance of mitochondrial electron transfer chain, reduced ROS production, and decreased membrane potential.

Type de document:Article publié dans une revue avec comité d'évaluation
Version évaluée par les pairs:Oui
Date:14 Mars 2018
Nombre de pages:1
Identifiant unique:10.1371/journal.pone.0193386
Sujets:Sciences naturelles et génie > Sciences naturelles > Chimie
Sciences de la santé > Sciences médicales > Pharmacologie
Département, module, service et unité de recherche:Départements et modules > Département des sciences fondamentales
Unités de recherche > Centre de recherche sur la Boréalie (CREB)
Mots-clés:apoptosis, non-small cell lung cancer, lung and intrathoracic tumors, mitochondria, cancer treatment, cytotoxicity, malonates, DNA fragmentation
Déposé le:13 nov. 2023 14:48
Dernière modification:13 nov. 2023 14:48
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