Betulinic acid as apoptosis activator: Molecular mechanisms, mathematical modeling and chemical modifications

Kumar, Pranesh; Bhadauria, Archana S.; Singh, Ashok Kumar; Saha, Sudipta

doi:10.1016/j.lfs.2018.07.056

Cited by 49 publications

(36 citation statements)

References 138 publications

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“…This suggests that compound 3 may activate a different pathway for apoptosis induction, independent of caspase activation, that still need to be investigated. On the other hand, similarly to observed after treatment of cancer cells with betulinic acid or friedelin-like molecules (Raghuvar et al, 2005;Subash-Babu et al, 2017;Kumar et al, 2018), compound 3 increased annexin V expression and induced a discrete increase in caspase 3/7 activity, suggesting that this compound may trigger the mitochondrial pathway. The exact mechanisms underpinning apoptosis triggered by compound 3 are still under investigation.…”

Section: Resultssupporting

confidence: 61%

“…Other structure related to pentacyclic triterpenes, such as betulinic, oleanolic and pomolic acids, present inhibitory effect on K562 proliferation (Fernandes et al, 2003), suggesting that triterpenes evaluated in this study may have a mechanism of action similar of those terpenoids (Kumar et al, 2018). Li et al (2010) have described that friedelin and other structure-related molecules inhibit HL-60 proliferation.…”

Section: Resultsmentioning

confidence: 66%

“…These molecules may trigger intrinsic apoptosis via different pathways. Moreover, betulinic acid may also trigger apoptosis in a caspase-independent fashion (Kumar et al, 2018). Herein, we have described that compound 2 have a inhibitory activity on cell proliferation (Figure 2) without changes on annexin V expression in the outer membrane ( Figure 5) and caspase 3/7 activity ( Figure 6).…”

Section: Resultsmentioning

confidence: 90%

“…On the other hand, we have observed a raise in 40% of caspase 3/7 + in 3 treated cells (from 2.03% in medium to 2.85% after treatment), when compared to cells cultured in medium alone, in agreement with proliferation and annexin V expression. Triterpenoids such as betulinic acid, friedelin, their derivatives and structure related molecules have antitumor activities (Peron et al, 2018;Kumar et al, 2018). These molecules may trigger intrinsic apoptosis via different pathways.…”

Section: Resultsmentioning

confidence: 99%

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Evaluation of cytotoxic activity of triterpenes from Clusia studartiana

Brito¹,

Carvalho²,

Silva³

et al. 2019

J. Med. Plants Res.

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Family Clusiaceae is spread throughout tropical as well as temperate zones, presenting many triterpenes, reported as selective antitumoral agents. The aim of this study is to isolate and identify triterpenes from Clusia studartiana C. M. Vieira & Gomes da Silva and evaluate their cytotoxicity in melanoma (SKMEL 28) and myeloid leukemia (K562) cell lines. Thus, the hexanic extract was processed by phytochemical methods to isolate and purify the pentacyclic triterpenes: 3-oxo-friedelin (1), 3-βhydroxy-friedelin (2) and 3-oxo-olean-12-en-28-oic-acid (3), identified by spectroscopic methods. Cytotoxicity was evaluated by MTT assay, apoptosis/necrosis by Annexin V/PI, caspase activity by FLICA in flow cytometry and P-gp modulation was measured by interference in the efflux of Rhodamine 123. From the results, triterpenes 2 and 3 showed inhibitory effect in K562 cells proliferation, and only the compound 3 was able to increase percentage of AnnexinV + PI in cells (p<0.05), with 40% increase in caspase 3/7 + cells and showed inhibition on P-gp activity.

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Section: Resultssupporting

confidence: 61%

Section: Resultsmentioning

confidence: 66%

Section: Resultsmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

Evaluation of cytotoxic activity of triterpenes from Clusia studartiana

Brito¹,

Carvalho²,

Silva³

et al. 2019

J. Med. Plants Res.

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“…BA is a natural product that possesses serious biological and pharmacological properties. The pentacyclic triterpene nucleus of BA comprises six isoprene units that exhibit a variety of biological activities, including antioxidative activity [33,34]. In this study, after giving the mice oral doses of 0.25, 0.5, or 1 mg/kg BA, or 100 mg/kg VE before exposure to T-2 toxin, the activities of CAT and SOD in the testis were higher, and the content of MDA in the testis was lower than in mice without BA treatment.…”

Section: Discussionmentioning

confidence: 99%

Betulinic Acid Attenuates T-2-Toxin-Induced Testis Oxidative Damage Through Regulation of the JAK2/STAT3 Signaling Pathway in Mice

Yang

Liu

et al. 2019

Biomolecules

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T-2 toxin is one of the most toxic type A trichothecene mycotoxins in nature, and it exhibits reproductive toxicity. Betulinic acid (BA) is a natural pentacyclic triterpene compound found in species of Betula, and it has been reported to have antioxidant activity. The aim of the present study was to investigate the protective effect of BA on T-2-toxin-induced testicular injury in mice and explore its molecular mechanism. Sixty adult male mice were randomly divided into groups. The mice were pretreated orally with BA (0.25, 0.5, and 1.0 mg/kg) daily for 14 days, and the T-2 toxin (4 mg/kg body weight) was administered via intraperitoneal injection to induce oxidative stress after the last administration of BA. BA pretreatment significantly increased the secreted levels of testosterone and sperm motility. Moreover, BA pretreatment significantly increased the total antioxidant capacity (T-AOC), the activity of SOD and CAT, and the content of GSH, and it reduced the content of MDA. Furthermore, BA relieved testicular injury and reduced the number of apoptotic cells, and it significantly decreased the protein expression of Janus kinase 2 (JAK2), signal transducers and activators of transcription 3 (STAT3), caspsae-3, and Bcl-2-associated X protein (Bax). BA also increased the expression of B-cell lymphoma-2 (Bcl-2). We suggest that BA reduced the oxidative damage induced by T-2 toxin, and that these protective effects may be partially mediated by the JAK2/STAT3 signaling pathway.

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