Triterpenoids with modified A-ring as modulators of P-gp-dependent drug-resistance in cancer cells

Rybalkina, Ekaterina Yu.; Моисеева, Н. И.; Карамышева, А. Ф.; Ерошенко, Д. В.; Konysheva, A. V.; Nazarov, Alexey V.; Гришко, В. В.

doi:10.1016/j.cbi.2021.109645

Cited by 17 publications

(21 citation statements)

References 59 publications

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“…Interestingly, the performed computing of the binding energies of investigated triterpenoids to ABC transporters revealed their high correlation with the level of doxorubicin uptake in triterpenoid-treated B16 cells: the efficiency of the binding of SM epoxides and SM to the mentioned efflux transporters decreased in the order αO-SM ≥ SM > βO-SM , as in the case of doxorubicin uptake assay (compare Figure 2 C,D). The obtained results agree with the published data; recently, Rybalkina et al demonstrated the ability of semisynthetic pentacyclic triterpenoids with modified ring A to inhibit the efflux activity of P-glycoprotein in multidrug resistant HBL-100/Dox cells [ 50 ].…”

Section: Resultssupporting

confidence: 90%

Novel Epoxides of Soloxolone Methyl: An Effect of the Formation of Oxirane Ring and Stereoisomerism on Cytotoxic Profile, Anti-Metastatic and Anti-Inflammatory Activities In Vitro and In Vivo

Salomatina

Sen’kova

Moralev

et al. 2022

IJMS

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It is known that epoxide-bearing compounds display pronounced pharmacological activities, and the epoxidation of natural metabolites can be a promising strategy to improve their bioactivity. Here, we report the design, synthesis and evaluation of biological properties of αO-SM and βO-SM, novel epoxides of soloxolone methyl (SM), a cyanoenone-bearing derivative of 18βH-glycyrrhetinic acid. We demonstrated that the replacement of a double-bound within the cyanoenone pharmacophore group of SM with α- and β-epoxide moieties did not abrogate the high antitumor and anti-inflammatory potentials of the triterpenoid. It was found that novel SM epoxides induced the death of tumor cells at low micromolar concentrations (IC50(24h) = 0.7–4.1 µM) via the induction of mitochondrial-mediated apoptosis, reinforced intracellular accumulation of doxorubicin in B16 melanoma cells, probably by direct interaction with key drug efflux pumps (P-glycoprotein, MRP1, MXR1), and the suppressed pro-metastatic phenotype of B16 cells, effectively inhibiting their metastasis in a murine model. Moreover, αO-SM and βO-SM hampered macrophage functionality in vitro (motility, NO production) and significantly suppressed carrageenan-induced peritonitis in vivo. Furthermore, the effect of the stereoisomerism of SM epoxides on the mentioned bioactivities and toxic profiles of these compounds in vivo were evaluated. Considering the comparable antitumor and anti-inflammatory effects of SM epoxides with SM and reference drugs (dacarbazine, dexamethasone), αO-SM and βO-SM can be considered novel promising antitumor and anti-inflammatory drug candidates.

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Section: Resultssupporting

confidence: 90%

Novel Epoxides of Soloxolone Methyl: An Effect of the Formation of Oxirane Ring and Stereoisomerism on Cytotoxic Profile, Anti-Metastatic and Anti-Inflammatory Activities In Vitro and In Vivo

Salomatina

Sen’kova

Moralev

et al. 2022

IJMS

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“…Presence of ortho-dihydroxy function in flavone C ring has been suggested to be important for antioxidant and anticancer activity (Raj et al, 2014) . Resin glycosides with acyl sugar coupled with amphiphilic nature have been reported to shown P-gp inhibition leading to overcoming MDR in cancer (Lira-Ricárdez J et al, 2020;Rybalkina et al, 2021;Syed et al, 2016). The present results of higher antioxidant activity leading to anticancer activity against breast cancer cell lines are in line with reports of plant phenolics in herbal medicine with strong antioxidant activity (Liaudanskas et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

“…Oxidative stress in causing changes in metabolic processes that trigger cancer cell proliferation and the role of quenching of free radical species has been found to be critical to control cancer (Pandey et al, 2009). Higher phenolic content from Scurrulaferruginea (Jack) Danser had shown to enhanced apoptosis in breast cancer cell lines, due to high level of radical quenching ability (Iriti et al, 2017;Marvibaigi et al, 2016;Rybalkina et al, 2021;Syed et al, 2016;Veena Sharma et al, 2017) . In view of the above, the anticancer activity of fraction W04 from Ipomoea aquatica, could be correlated with high phenolic content through its antioxidant activity.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Role of Merromoside from Ipomoea aquatica Forsskal Hydroalcoholic Extract in the Downregulation of ROS Species in Overcoming MDR in Breast Cancer

Sasikala

Mohan

Swarnakumari

et al. 2022

Asian Pac J Cancer Prev

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the global exigency through drug development and research (Apu et al., 2012). The International Agency for Research on Cancer (IARC) estimates that globally, 1 in 5 people develop cancer during their lifetime, and 1 in 8 men and 1 in 11 women die from the disease. Breast cancer represents 1 in 4 cancers diagnosed among women globally. Colorectal, lung, cervical, and thyroid cancers are also common among women (MamtaSaxena et al., 2013;Marvibaigi et al., 2016) . As per the report on the plant, Convolvulaceae plants would have resin glycosides like aquaterins, convolvulins and jalapins (Ono, 2017) . Aquaterins (I to XIX) present in the I. aquatica plant had evaluated for aquaterin II induced G0/ G1 arrest regulated by related proteins CDK4/6, cyclin

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“…K562/i-S9 cell line was kindly provided by Mechetner [ 45 ]. In our laboratory of tumor cell genetics, we were derived a doxorubicin-resistant cell subline of Pgp and ABCG2 (BCRP) overexpressing HBL-100/Dox cell line from the HBL-100 cells (received from Institute of Cytology RAS) after the continuous cell selection in the presence of Dox [ 46 ]. HBL-100/Dox cell was used as a positive control for anti-ABCG2 antibody performance.…”

Section: Methodsmentioning

confidence: 99%

Analysis of Multiple Drug Resistance Mechanism in Different Types of Soft Tissue Sarcomas: Assessment of the Expression of ABC-Transporters, MVP, YB-1, and Analysis of Their Correlation with Chemosensitivity of Cancer Cells

Моисеева¹,

Laletina²,

Fetisov³

et al. 2022

IJMS

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Chemotherapy of soft tissue sarcomas (STS) is restricted by low chemosensitivity and multiple drug resistance (MDR). The purpose of our study was the analysis of MDR mechanism in different types of STS. We assessed the expression of ABC-transporters, MVP, YB-1, and analyzed their correlation with chemosensitivity of cancer cells. STS specimens were obtained from 70 patients without metastatic disease (2018–2020). Expression level of MDR-associated genes was estimated by qRT-PCR and cytofluorimetry. Mutations in ABC-transporter genes were captured by exome sequencing. Chemosensitivity (SI) of STS to doxorubicin (Dox), ifosfamide (Ifo), gemcitabine (Gem), and docetaxel (Doc) was analyzed in vitro. We found strong correlation in ABCB1, ABCC1, and ABCG2 expression. We demonstrated strong negative correlations in ABCB1 and ABCG2 expression with SI (Doc) and SI (Doc + Gem), and positive correlation of MVP expression with SI (Doc) and SI (Doc + Gem) in undifferentiated pleomorphic sarcoma. Pgp expression was shown in 5 out of 44 STS samples with prevalence of synovial sarcoma relapses and it is strongly correlated with SI (Gem). Mutations in MDR-associated genes were rarely found. Overall, STS demonstrated high heterogeneity in chemosensitivity that makes reasonable in vitro chemosensitivity testing to improve personalized STS therapy, and classic ABC-transporters are not obviously involved in MDR appearance.

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Triterpenoids with modified A-ring as modulators of P-gp-dependent drug-resistance in cancer cells

Cited by 17 publications

References 59 publications

Novel Epoxides of Soloxolone Methyl: An Effect of the Formation of Oxirane Ring and Stereoisomerism on Cytotoxic Profile, Anti-Metastatic and Anti-Inflammatory Activities In Vitro and In Vivo

Novel Epoxides of Soloxolone Methyl: An Effect of the Formation of Oxirane Ring and Stereoisomerism on Cytotoxic Profile, Anti-Metastatic and Anti-Inflammatory Activities In Vitro and In Vivo

Evaluation of the Role of Merromoside from Ipomoea aquatica Forsskal Hydroalcoholic Extract in the Downregulation of ROS Species in Overcoming MDR in Breast Cancer

Analysis of Multiple Drug Resistance Mechanism in Different Types of Soft Tissue Sarcomas: Assessment of the Expression of ABC-Transporters, MVP, YB-1, and Analysis of Their Correlation with Chemosensitivity of Cancer Cells

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