Betulinic acid induces apoptosis and suppresses metastasis in hepatocellular carcinoma cell lines in vitro and in vivo

Wang, Wei; Wang, Yang; Liu, Mingxing; Zhang, Yifan; Yang, Tao; Li, Dongsheng; Huang, Yunmao; Li, Qing; Bai, Guang; Shi, Linlin

doi:10.1111/jcmm.13964

Cited by 28 publications

(28 citation statements)

References 39 publications

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“…BA has many pharmacological activities, including tumor suppression and anti‐inflammatory effects 29,30,44 . It has been showed to induce apoptosis and suppress metastasis in HCC cells and HepG2 xenograft mice 45 . Consistent with this, we demonstrated that BA inhibited tumor progression and invasion in orthotopic HCC mice.…”

Section: Discussionsupporting

confidence: 87%

Suppression of lncRNA MALAT1 by betulinic acid inhibits hepatocellular carcinoma progression by targeting IAPs via miR‐22‐3p

Chen

Zhong

Tan

et al. 2020

Clinical & Translational Med

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Betulinic acid (BA) is a natural product extracted from a broad range of medicinal and edible herbal plants. Previous studies showed that BA induces cell death in tumors derived from multiple tissues; however, the underlying mechanism remains obscure. The present study aimed to study the effects of BA on autophagy and apoptosis of hepatocellular carcinoma (HCC). Human HCC cell lines and orthotopic HCC implanted mice were employed to examine the BA‐induced tumor suppression; RT 2 long noncoding RNA (lncRNA) PCR array and database analysis were used to explore the possible mechanisms; validation of pathways was performed using siRNA and miRNA inhibitors. The results indicated that BA regulated autophagy and induced apoptosis in HCC. The degradation of inhibitor of apoptosis proteins (IAPs), the conversion of LC3‐I to LC3‐II, and p62 accumulation were enhanced by BA, thereby suggesting that the downregulation of IAPs and autophagic cell death are induced by BA. The addition of autophagy and lysosomal inhibitors indicated that BA induced autophagy‐independent apoptosis via degradation of IAPs. Moreover, RT 2 lncRNA PCR array and database analysis suggested that BA downregulated the levels of lncRNA MALAT1, which is considered to be an oncogene. Further investigations demonstrated that lncRNA MALAT1 functioned as a ceRNA (competing endogenous RNA) to contribute to BA‐mediated degradation of IAPs by sponging miR‐22‐3p. Therefore, BA could be developed as a potential anticancer agent for HCC.

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Section: Discussionsupporting

confidence: 87%

Suppression of lncRNA MALAT1 by betulinic acid inhibits hepatocellular carcinoma progression by targeting IAPs via miR‐22‐3p

Chen

Zhong

Tan

et al. 2020

Clinical & Translational Med

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“…The cells were treated with betulinic acid after the cells growth can be visible to the naked eye. After 24 h of treatment, cell colonies were fixed with formaldehyde and stained with crystal violet for counting [9].…”

Section: Colony Formation Assaymentioning

confidence: 99%

“…Formaldehyde and 0.5% crystal violet (Sigma) were then used to fix and stain the invaded cells in correct order. To ensure the accuracy of the counting, five random fields under a microscope were selected to calculate the number of invaded cells [9].…”

Section: Transwell Assaymentioning

confidence: 99%

Chemopreventive effect of Betulinic acid via mTOR -Caspases/Bcl2/Bax apoptotic signaling in pancreatic cancer

Guo

Zhu

Wang

et al. 2020

BMC Complement Med Ther

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Background: Pancreatic cancer is aggressive with no symptoms until the advanced stage reached. The increased resistance of pancreatic cancer to chemotherapy demonstrates a dilemma in the clinical field. Hence, it is a matter of great urgency to develop an effective drug to treat patients with pancreatic cancer. Betulinic acid is a major triterpene isolated from spina date seed. Several studies have suggested its low toxicity and side effects to patients with malaria and inflammation. However, relevant studies on betulinic acid in inhibiting cancer were insufficient and the molecular mechanism was unclear. This study aimed to systematically explore the potential anti-cancer functions of betulinic acid in pancreatic cancer, and investigate its underlying molecular mechanism. Methods: The Counting Kit-8 assay, colony formation, transwell invasion assay, wound healing assay, flow cytometry and xenograft nude mice model were used to evaluate the effect of betulinic acid on the proliferation, invasion and migration ability of pancreatic cancer cells. Results: Our results showed that betulinic acid obviously suppressed pancreatic cancer both in vitro and in vivo in a dose-dependent manner. We also determined that betulinic acid inhibited pancreatic cancer by specifically targeting mTOR signaling rather than Nrf2 or JAK2. Conclusions: These findings clarify that betulinic acid is a potential and valuable anticancer agent for pancreatic cancer, and indicate the specific molecular target of betulinic acid.

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“…Betulinic acid (BA), a naturally occurring pentacyclic triterpenoid in the bark of plane and birch trees, has been demonstrated to exert a variety of biological features. In addition to its anti-HIV [1], antiparasitic [2] and antiinflammatory [3] properties, BA shows anticancer activity in vitro and in vivo [4][5][6][7][8][9][10]. Its antitumor effects are mediated mainly by a CD95-and p53-independent induction of apoptosis [11].…”

Section: Introductionmentioning

confidence: 99%

Betulinic acid shows anticancer activity against equine melanoma cells and permeates isolated equine skin in vitro

et al. 2020

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Background: Equine malignant melanoma (EMM) is a frequently occurring dermoepidermal tumor in grey horses. Currently available therapies are either challenging or inefficient. Betulinic acid (BA), a naturally occurring triterpenoid, is a promising compound for cancer treatment. To evaluate the potential of BA as a topical therapy for EMM, its anticancer effects on primary equine melanoma cells and dermal fibroblasts and its percutaneous permeation through isolated equine skin were assessed in vitro. Results: BA showed antiproliferative and cytotoxic effects on both primary equine melanoma cells and fibroblasts in a time-and dose-dependent manner. The lowest half-maximal inhibitory concentrations were obtained 96 h after the beginning of drug exposure (12.7 μmol/L and 23.6 μmol/L for melanoma cells eRGO1 and MelDuWi, respectively, in cytotoxicity assay). High concentrations of the compound were reached in the required skin layers in vitro. Conclusion: BA is a promising substance for topical EMM treatment. Further clinical studies in horses are necessary to assess safety and antitumoral effects in vivo.

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Betulinic acid induces apoptosis and suppresses metastasis in hepatocellular carcinoma cell lines in vitro and in vivo

Cited by 28 publications

References 39 publications

Suppression of lncRNA MALAT1 by betulinic acid inhibits hepatocellular carcinoma progression by targeting IAPs via miR‐22‐3p

Suppression of lncRNA MALAT1 by betulinic acid inhibits hepatocellular carcinoma progression by targeting IAPs via miR‐22‐3p

Chemopreventive effect of Betulinic acid via mTOR -Caspases/Bcl2/Bax apoptotic signaling in pancreatic cancer

Betulinic acid shows anticancer activity against equine melanoma cells and permeates isolated equine skin in vitro

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