Synthesis and antiproliferative evaluation of 23-hydroxybetulinic acid derivatives

Lan, Ping; Wang, Jiao; Zhang, Dongmei; Shu, Chang; Cao, Hongxin; Sun, Ping‐Hua; Wu, Xiaoming; Ye, Wen‐Cai; Chen, Weimin

doi:10.1016/j.ejmech.2011.03.038

Cited by 33 publications

(31 citation statements)

References 26 publications

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“…Recently, the modification of natural products from TCM has become a promising approach for novel drug development. To enhance the antitumour efficacy of 23-HBA and reduce its side effects, we performed a series of structural modifications of 23-HBA and conducted a bioactivity screening [24]. We found that a piperazidine derivative of 23-HBA, B5G9, showed excellent anti-HCC activity both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

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A piperazidine derivative of 23-hydroxy betulinic acid induces a mitochondria-derived ROS burst to trigger apoptotic cell death in hepatocellular carcinoma cells

Yao

Lei

et al. 2016

J Exp Clin Cancer Res

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BackgroundElevated production of reactive oxygen species (ROS) and an altered redox state have frequently been observed in hepatocellular carcinoma (HCC); therefore, selective killing of HCC cells by chemotherapeutic agents that stimulate ROS generation or impair antioxidant systems may be a feasible approach in HCC chemotherapy. Recently, betulinic acid and its derivatives have attracted attention because they showed anti-cancer effects via a ROS- and mitochondria-related mechanism. However, the source of ROS overproduction and the role of mitochondria were poorly identified, and the weak in vivo antitumour activity of these compounds limits their development as drugs.MethodsCytotoxicity was detected using MTT assays. In vivo anti-HCC effects were assessed using nude mice bearing HepG2 tumour xenografts. Cell cycle analysis, apoptosis rate and mitochondrial membrane potential were measured by flow cytometry. ROS production was detected using a microplate reader or a fluorescence microscope. Changes in gene and protein levels were measured by RT-PCR and western blotting, respectively. Other assays were performed using related detection kits.ResultsB5G9, a piperazidine derivative of 23-hydroxy betulinic acid (23-HBA), showed excellent in vivo anti-HCC effects, with a tumour growth inhibitory rate of greater than 80%, and no significant side effects. B5G9 stimulated the production of ROS, which were derived from the mitochondria, but it had no effect on various other antioxidant systems. Moreover, B5G9 induced mitochondrial dysfunction, which was characterized by morphological changes, membrane potential collapse, membrane permeabilization, and decreases in the O2 consumption rate and ATP production. Furthermore, mtDNA-depleted ρ0 HepG2 cells were less sensitive to B5G9 treatment than wt HepG2 cells, indicating the importance of mitochondria in B5G9-induced cell death.ConclusionWe discovered a piperazidine derivative of 23-HBA, B5G9, with excellent anti-HCC effects both in vivo and in vitro and no obvious toxic effects. The underlying mechanism was associated with mitochondria-derived ROS overproduction, and mitochondria played essential roles in B5G9-induced cell death. This study identified a potential agent for anti-HCC therapy and elucidated the mitochondria-related mechanism of BA and its derivatives.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0457-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

“…B5G9 with a purity of 98% was synthesized as described previously [24]. Hoechst 33342, H 2 DCFDA, MitoTracker® Red CMXRos, MitoSOX Red, a BCA protein assay kit and a Dead Cell Apoptosis Kit were purchased from Thermo Fisher Scientific (Waltham, MA, USA).…”

Section: Methodsmentioning

confidence: 99%

A piperazidine derivative of 23-hydroxy betulinic acid induces a mitochondria-derived ROS burst to trigger apoptotic cell death in hepatocellular carcinoma cells

Yao

Lei

et al. 2016

J Exp Clin Cancer Res

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“…The BBA was synthesized, and isolated in the powder form using chromatography with a purity of > 98%, and solved in dimethyl sulfoxide (DMSO) as described previously [24]. The chemical structure of BBA is shown in Figure 1 Cepharanthine was generously provided by Daiichi Sankyo Pharmaceutical Co. Ltd (Tokyo, Japan).…”

Section: Methodsmentioning

confidence: 99%

BBA, a Synthetic Derivative of 23-hydroxybutulinic Acid, Reverses Multidrug Resistance by Inhibiting the Efflux Activity of MRP7 (ABCC10)

et al. 2013

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Natural products are frequently used for adjuvant chemotherapy in cancer treatment. 23-O-(1,4'-bipiperidine-1-carbonyl) betulinic acid (BBA) is a synthetic derivative of 23-hydroxybutulinic acid (23-HBA), which is a natural pentacyclic triterpene and the major active constituent of the root of Pulsatilla chinensis . We previously reported that BBA could reverse P-glycoprotein (P-gp/ABCB1)-mediated multidrug resistance (MDR). In the present study, we investigated whether BBA has the potential to reverse multidrug resistance protein 7 (MRP7/ABCC10)-mediated MDR. We found that BBA concentration-dependently enhanced the sensitivity of MRP7-transfected HEK293 cells to paclitaxel, docetaxel and vinblastine. Accumulation and efflux experiments demonstrated that BBA increased the intracellular accumulation of [3H]-paclitaxel by inhibiting the efflux of [3H]-paclitaxel from HEK293/MRP7 cells. In addition, immunoblotting and immunofluorescence analyses indicated no significant alteration of MRP7 protein expression and localization in plasma membranes after treatment with BBA. These results demonstrate that BBA reverses MRP7-mediated MDR through blocking the drug efflux function of MRP7 without affecting the intracellular ATP levels. Our findings suggest that BBA has the potential to be used in combination with conventional chemotherapeutic agents to augment the response to chemotherapy.

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“…Until now, there have been no report on the anti-hepatoma activity of 23-HBA. Given that 23-HBA has weak anticancer activity, our effort to improve its antitumour activity by structural modification has yielded a series of derivatives with enhanced bioactivity [19][20][21][22]. B4G2, a derivative of 23-HBA, was previously synthesized by our group and showed a stronger anticancer activity than 23-HBA in four cancer cell lines in preliminary activity screening [20].…”

Section: Introductionmentioning

confidence: 99%

B4G2 Induces Mitochondrial Apoptosis by the ROS-Mediated Opening of Ca2+-Dependent Permeability Transition Pores

Yao

Zhang

et al. 2015

Cell Physiol Biochem

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Background/Aims: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. At present, only sorafenib is approved to treat HCC. In this study, we found that a 23-hydroxybetulinic acid derivative, B4G2, exhibited potent antiproliferative activity in HCC cell lines. Methods: We used four HCC cell lines (HepG2, HepG2/ADM, Hep3B and Bel-7402) to evaluate the anti-tumour activity and explore underlying mechanisms by which B4G2 induces apoptosis. Results: Among these cell lines, HepG2 showed the highest sensitivity to B4G2. HepG2 cells treated with B4G2 showed a depolarized mitochondrial membrane potential, released cytochrome c, activated caspase-9 and caspase-3 and cleaved poly ADP-ribose polymerase (PARP). However, Z-VAD-FMK, a pan-caspase inhibitor, did not attenuate B4G2-induced apoptosis, implying that the induction of mitochondrial apoptosis by B4G2 may be independent of caspases. Moreover, pre-treatment with MgCl₂, a blocker of Ca²⁺-dependent permeability transition (PT) pores, attenuated the depolarization of the mitochondrial potential and decreased the population of apoptotic cells, indicating that B4G2-induced apoptosis was partly dependent on the opening of the Ca²⁺-dependent PT pores. B4G2 also increased the levels of intracellular calcium and reactive oxygen species (ROS). Furthermore, an ROS scavenger, N-acetyl-cysteine (NAC), markedly decreased the accumulation of intracellular calcium and apoptosis. Conclusion: This is the first demonstration that B4G2 inhibits the growth of HCC cells and induces mitochondrial apoptosis in hepatocellular carcinoma cells by the ROS-mediated opening of Ca²⁺-dependent permeability transition pores.

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Synthesis and antiproliferative evaluation of 23-hydroxybetulinic acid derivatives

Cited by 33 publications

References 26 publications

A piperazidine derivative of 23-hydroxy betulinic acid induces a mitochondria-derived ROS burst to trigger apoptotic cell death in hepatocellular carcinoma cells

A piperazidine derivative of 23-hydroxy betulinic acid induces a mitochondria-derived ROS burst to trigger apoptotic cell death in hepatocellular carcinoma cells

BBA, a Synthetic Derivative of 23-hydroxybutulinic Acid, Reverses Multidrug Resistance by Inhibiting the Efflux Activity of MRP7 (ABCC10)

B4G2 Induces Mitochondrial Apoptosis by the ROS-Mediated Opening of Ca2+-Dependent Permeability Transition Pores

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