Biotechnological production of betulinic acid and derivatives and their applications

An, Tianyue; Zha, Wenlong; Zi, Jiachen

doi:10.1007/s00253-020-10495-1

Cited by 25 publications

(14 citation statements)

References 76 publications

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“…(Rastogi et al 2015 ; Ríos and Máñez 2018 ). Accumulated evidence demonstrates that BA possesses various biological activities, including antioxidant, anti-inflammatory, hepatoprotective, and anti-tumor effects (Saneja et al 2018 ; An et al, 2020 ; Li et al 2021 ; Kong et al 2021 ). Among them, the anti-tumor potential has recently received great attention, showing that the anti-cancer mechanisms of BA are complex and depends on the type of cancer cells, without causing toxicity toward normal cells (Mullauer et al 2010 ; Gheorgheosu et al 2014 ; Kumar et al 2018 ; Zuco et al 2020 ; Kutkowska et al 2021 ).…”

Section: Introductionmentioning

confidence: 99%

The anti-cancer effect of betulinic acid in u937 human leukemia cells is mediated through ROS-dependent cell cycle arrest and apoptosis

Park

Jeong

Han

et al. 2021

Animal Cells and Systems

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Although previous studies have shown anti-cancer activity of betulinic acid (BA), a pentacyclic triterpenoid, against various cancer lines, the underlying molecular mechanisms are not well elucidated. In this study, we evaluated the mechanisms involved in the anti-cancer efficacy of BA in U937 human myeloid leukemia cells. BA exerted a significant cytotoxic effect on U937 cells through blocking cell cycle arrest at the G2/M phase and inducing apoptosis, and that the intracellular reactive oxygen species (ROS) levels increased after treatment with BA. The down-regulation of cyclin A and cyclin B1, and up-regulation of cyclin-dependent kinase inhibitor p21WAF1/CIP1 revealed the G2/M phase arrest mechanism of BA. In addition, BA induced the cytosolic release of cytochrome c by reducing the mitochondrial membrane potential with an increasing Bax/Bcl-2 expression ratio. BA also increased the activity of caspase-9 and -3, and subsequent degradation of the poly (ADP-ribose) polymerase. However, quenching of ROS by N -acetyl-cysteine, an ROS scavenger, markedly abolished BA-induced G2/M arrest and apoptosis, indicating that the generation of ROS plays a key role in inhibiting the proliferation of U937 cells by BA treatment. Taken together, our results provide a mechanistic rationale that BA exhibits anti-cancer properties in U937 leukemia cells through ROS-dependent induction of cell cycle arrest at G2/M phase and apoptosis.

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Section: Introductionmentioning

confidence: 99%

The anti-cancer effect of betulinic acid in u937 human leukemia cells is mediated through ROS-dependent cell cycle arrest and apoptosis

Park

Jeong

Han

et al. 2021

Animal Cells and Systems

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“…As a lupane-type triterpenoid produced in birch plants, betulinic acid and its derivatives have been demonstrated to have potent anticancer and anti-HIV activities in numerous studies. To date, the biosynthetic pathway of betulinic acid has been completely mapped, and its commercial production is through phytochemical extraction and semi-synthesis from its precursor, betulin [81]. Natural plant-derived betulinic acid exhibited tumorselective inhibitory activity and could induce apoptosis of a wide variety of cancer cells, mostly through a mitochondrion-dependent mechanism [82][83][84][85].…”

Section: Betulinic Acid-mediated Inhibition Of Fatty Acid Desaturationmentioning

confidence: 99%

Phytochemicals Block Glucose Utilization and Lipid Synthesis to Counteract Metabolic Reprogramming in Cancer Cells

Zhao

Sui

et al. 2021

Applied Sciences

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Aberrant metabolism is one of the hallmarks of cancers. The contributions of dysregulated metabolism to cancer development, such as tumor cell survival, metastasis and drug resistance, have been extensively characterized. “Reprogrammed” metabolic pathways in cancer cells are mainly represented by excessive glucose consumption and hyperactive de novo lipogenesis. Natural compounds with anticancer activities are constantly being demonstrated to target metabolic processes, such as glucose transport, aerobic glycolysis, fatty acid synthesis and desaturation. However, their molecular targets and underlying anticancer mechanisms remain largely unclear or controversial. Mounting evidence indicated that these natural compounds could modulate the expression of key regulatory enzymes in various metabolic pathways at transcriptional and translational levels. Meanwhile, natural compounds could also inhibit the activities of these enzymes by acting as substrate analogs or altering their protein conformations. The actions of natural compounds in the crosstalk between metabolism modulation and cancer cell destiny have become increasingly attractive. In this review, we summarize the activities of natural small molecules in inhibiting key enzymes of metabolic pathways. We illustrate the structural characteristics of these compounds at the molecular level as either inhibitor of various enzymes or regulators of metabolic pathways in cancer cells. Our ultimate goal is to both facilitate the clinical application of natural compounds in cancer therapies and promote the development of novel anticancer therapeutics.

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“…Betulinic acid is a pentacyclic triterpene and is used as an antitumor, antiviral, and anti-inflammatory agent (An et al, 2020). The highest titer of betulinic acid production obtained using S. cerevisiae was reported to be 182 mg/L by combining metabolic and process engineering (Czarnotta et al, 2017).…”

Section: Betulinic Acid (Triterpene)mentioning

confidence: 99%

Current Challenges and Opportunities in Non-native Chemical Production by Engineered Yeasts

Kim

Tran

Lee

2020

Front. Bioeng. Biotechnol.

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Yeasts are promising industrial hosts for sustainable production of fuels and chemicals. Apart from efficient bioethanol production, yeasts have recently demonstrated their potential for biodiesel production from renewable resources. The fuel-oriented product profiles of yeasts are now expanding to include non-native chemicals with the advances in synthetic biology. In this review, current challenges and opportunities in yeast engineering for sustainable production of non-native chemicals will be discussed, with a focus on the comparative evaluation of a bioethanol-producing Saccharomyces cerevisiae strain and a biodiesel-producing Yarrowia lipolytica strain. Synthetic pathways diverging from the distinctive cellular metabolism of these yeasts guide future directions for product-specific engineering strategies for the sustainable production of non-native chemicals on an industrial scale.

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Biotechnological production of betulinic acid and derivatives and their applications

Cited by 25 publications

References 76 publications

The anti-cancer effect of betulinic acid in u937 human leukemia cells is mediated through ROS-dependent cell cycle arrest and apoptosis

The anti-cancer effect of betulinic acid in u937 human leukemia cells is mediated through ROS-dependent cell cycle arrest and apoptosis

Phytochemicals Block Glucose Utilization and Lipid Synthesis to Counteract Metabolic Reprogramming in Cancer Cells

Current Challenges and Opportunities in Non-native Chemical Production by Engineered Yeasts

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