Betulinic Acid Inhibits Prostate Cancer Growth through Inhibition of Specificity Protein Transcription Factors

Chintharlapalli, Sudhakar; Papineni, Sabitha; Ramaiah, Shashi K.; Safe, Stephen

doi:10.1158/0008-5472.can-06-3735

Cited by 273 publications

(339 citation statements)

References 45 publications

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“…Betulinic acid (BA), a natural pentacyclic triterpene isolated from birch, exhibits a variety of biological activities, including anti-HIV, anti-HBV, anti-malarial [8][9][10] and potent anti-tumor properties in melanoma [11] , leukemia [12] , colon [13] , lung [14] , gliomas [15] , prostate carcinoma [16] , gastric adenocarcinoma [17] and multiple myeloma [18,19] . Various mechanisms have been reported for the extensive anticancer activity of BA, including directly triggering mitochondrial membrane permeabilization [20] , regulating Bcl-2 family proteins [21] , downregulating Hiwi expression [17] and suppressing the activation of the STAT3 pathway through the induction of the protein tyrosine phosphatase SHP-1 [19] .…”

Section: Introductionmentioning

confidence: 99%

Betulinic acid inhibits autophagic flux and induces apoptosis in human multiple myeloma cells in vitro

Yang

Yan

et al. 2012

Acta Pharmacol Sin

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Aim: To investigate the effects of betulinic acid (BA) on apoptosis and autophagic flux in multiple myeloma cells and the relationship between the two processes. Methods: The proliferation of human multiple myeloma KM3 cells was measured with MTT assay. FITC/PI double-labeled flow cytometry (FCM) and Hoechst 33258 staining were used to analyze the cell apoptosis. Caspase 3, PARP, Beclin1, LC3-II, and P62 were detected using Western blotting. Results: Treatment of KM3 cells with BA (5−25 μg/mL) suppressed the cell proliferation in time-and dose-dependent manners. The IC 50 values at 12, 24, and 36 h were 22.29, 17.36, and 13.06 μg/mL, respectively. BA treatment dose-dependently induced apoptosis of KM3 cells, which was associated with the activation of caspase 3. However, Z-DEVD-FMK, a specific inhibitor of caspase 3, did not decrease, but rather sensitized the cells to BA-induced apoptosis, suggesting an alternative mechanism involved. On other hand, BA treatment dose-dependently increased the accumulation of LC3-II and P62 in KM3 cells, representing the inhibition of autophagic flux. Furthermore, BA treatment dose-dependently downregulated the expression of Beclin 1, an important inducer of autophagy, in KM3 cells. In the presence of BA, Z-DEVD-FMK induced autophagy and increased the amount of LC3-II in KM3 cells, which may occur via attenuating BA-induced decrease in the level of Beclin 1. Similarly, rapamycin, an autophagy inducer, increased the amount of LC3-II in KM3 cells. In the presence of BA, rapamycin caused further increase in the amount of LC3-II. Furthermore, rapamycin sensitized BA-treated KM3 cells to apoptosis. Conclusion:The results demonstrate that BA induces apoptosis and blocks autophagic flux in KM3 cells. Furthermore, in addition to activation of caspase 3, the inhibition of autophagic flux also contributes to the BA-mediated apoptosis of KM3 cells.

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Section: Introductionmentioning

confidence: 99%

Betulinic acid inhibits autophagic flux and induces apoptosis in human multiple myeloma cells in vitro

Yang

Yan

et al. 2012

Acta Pharmacol Sin

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“…Betulinic acid, a pentacyclic terterpene, and its derivatives have been reported to possess a variety of biological properties (Yogeeswari and Sriram, 2005) (Soler et al, 1996), anti-bacterial, anti-cancer (Chintharlapalli et al, 2007;Fulda, 2008), and anti-infl ammatory activities (Recio et al, 1995). Although anti-HIV and anti-cancer activities of betulinic acid and its derivatives have been reported to be through the inhibition of HIV entry, HIV-proteases or reverse transcriptase (Fujioka et al, 1994;Yogeeswari and Sriram, 2005), and through increased degradation of the transcription factors specifi city protein 1 (Sp1), Sp3, and Sp4 (Chintharlapalli et al, 2007), respectively, the underlying mechanism of anti-infl ammatory property of betulinic acid has not been clearly demonstrated (Recio et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…Although anti-HIV and anti-cancer activities of betulinic acid and its derivatives have been reported to be through the inhibition of HIV entry, HIV-proteases or reverse transcriptase (Fujioka et al, 1994;Yogeeswari and Sriram, 2005), and through increased degradation of the transcription factors specifi city protein 1 (Sp1), Sp3, and Sp4 (Chintharlapalli et al, 2007), respectively, the underlying mechanism of anti-infl ammatory property of betulinic acid has not been clearly demonstrated (Recio et al, 1995). The present results evidently demonstrate that betulinic acid signifi cantly suppresses the activity of transcription factor NF-kB, which has been reported to play a key role in the infl ammatory responses, through the inhibition of LPS-induced IKB degradation in the cytoplasm (Lee et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Betulinic Acid Inhibits LPS-Induced MMP-9 Expression by Suppressing NF-kB Activation in BV2 Microglial Cells

Kim

2011

Biomolecules and Therapeutics

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“…Subsequent studies with BetA showed selective cytotoxicity on a variety of tumor cell lines but not on normal cells [44] and induced apoptosis in neuroblastoma and glioblastoma cells through the activation of the mitochondrial pathway [45,46]. Interestingly, a report by Tan showed that BetA inhibited prostate cancer growth through inhibition of the transcription factors, specificity protein1 (Sp1), Sp3, and Sp4 which regulate VEGF and survivin expression [49]. Furthemore, BetA has been shown to inhibit constitutive activation of STAT3, Src kinase, JAK1 and JAK2 and induce the expression of the protein tyrosine phosphatase, SHP-1.…”

Section: Betulinic Acidmentioning

confidence: 99%

Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer

et al. 2012

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a b s t r a c tOver the last two decades, extensive research on plant-based medicinal compounds has revealed exciting and important pharmacological properties and activities of triterpenoids. Fruits, vegetables, cereals, pulses, herbs and medicinal plants are all considered to be biological sources of these triterpenoids, which have attracted great attention especially for their potent anti-inflammatory and anti-cancer activities. Published reports in the past have described the molecular mechanism(s) underlying the various biological activities of triterpenoids which range from inhibition of acute and chronic inflammation, inhibition of tumor cell proliferation, induction of apoptosis, suppression of angiogenesis and metastasis. However systematic analysis of various pharmacological properties of these important classes of compounds has not been done. In this review, we describe in detail the pre-clinical chemopreventive and therapeutic properties of selected triterpenoids that inhibit multiple intracellular signaling molecules and transcription factors involved in the initiation, progression and promotion of various cancers. Molecular targets modulated by these triterpenoids comprise, cytokines, chemokines, reactive oxygen intermediates, oncogenes, inflammatory enzymes such as COX-2, 5-LOX and MMPs, anti-apoptotic proteins, transcription factors such as NF-jB, STAT3, AP-1, CREB, and Nrf2 (nuclear factor erythroid 2-related factor) that regulate tumor cell proliferation, transformation, survival, invasion, angiogenesis, metastasis, chemoresistance and radioresistance. Finally, this review also analyzes the potential role of novel synthetic triterpenoids identified recently which mimic natural triterpenoids in physical and chemical properties and are moving rapidly from bench to bedside research.

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Betulinic Acid Inhibits Prostate Cancer Growth through Inhibition of Specificity Protein Transcription Factors

Cited by 273 publications

References 45 publications

Betulinic acid inhibits autophagic flux and induces apoptosis in human multiple myeloma cells in vitro

Betulinic acid inhibits autophagic flux and induces apoptosis in human multiple myeloma cells in vitro

Betulinic Acid Inhibits LPS-Induced MMP-9 Expression by Suppressing NF-kB Activation in BV2 Microglial Cells

Targeted inhibition of tumor proliferation, survival, and metastasis by pentacyclic triterpenoids: Potential role in prevention and therapy of cancer

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