A novel derivative of betulinic acid, SYK023, suppresses lung cancer growth and malignancy

Hsu, Todd; Chen, Ying Jung; Hung, Cheng‐Yuan; Wang, Yi Chang; Lin, Sin Jin; Su, Wu Chou; Lai, Ming Derg; Kim, Sang Yong; Wang, Qiang; Qian, Keduo; Goto, Masuo; Zhao, Yu; Kashiwada, Yoshiki; Lee, Kuo Hsiung̀; Chang, Wen Chang; Hung, Jan Jong

doi:10.18632/oncotarget.3701

Cited by 27 publications

(16 citation statements)

References 59 publications

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“…Further supporting our pathway analysis, drug resistance profiles in AA included drugs linked to stem cell and invasion pathways, including betulinic acid, rosiglitazone, and adiphenine. For example, betulinic acid and its derivative have been shown to target cancer stem cells and also have anticancer potential in NSCLC (48)(49)(50). Rosiglitazone, a thiazolidinedione used to treat diabetes, has demonstrated both antitumor and chemopreventive effects (51,52) and is also linked with stem cell signaling (53,54).…”

Section: Discussionmentioning

confidence: 99%

Comparative Transcriptome Profiling Reveals Coding and Noncoding RNA Differences in NSCLC from African Americans and European Americans

Mitchell

Zingone

Toulabi

et al. 2017

Clinical Cancer Research

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To determine whether racial differences in gene and miRNA expression translates to differences in lung tumor biology with clinical relevance in African Americans (AAs) and European Americans (EAs). The NCI-Maryland Case Control Study includes seven Baltimore City hospitals and is overrepresented with AA patients (∼40%). Patients that underwent curative NSCLC surgery between 1998 and 2014 were enrolled. Comparative molecular profiling used mRNA ( = 22 AAs and 19 EAs) and miRNA ( = 42 AAs and 55 EAs) expression arrays to track differences in paired fresh frozen normal tissues and lung tumor specimens from AAs and EAs. Pathway enrichment, predicted drug response, tumor microenvironment infiltration, cancer immunotherapy antigen profiling, and miRNA target enrichment were assessed. AA-enriched differential gene expression was characterized by stem cell and invasion pathways. Differential gene expression in lung tumors from EAs was primarily characterized by cell proliferation pathways. Population-specific gene expression was partly driven by population-specific miRNA expression profiles. Drug susceptibility predictions revealed a strong inverse correlation between AA resistance and EA sensitivity to the same panel of drugs. Statistically significant differences in M1 and M2 macrophage infiltration were observed in AAs ( < 0.05); however, expression was similar between both. Comparative transcriptomic profiling revealed clear differences in lung tumor biology between AAs and EAs. Increased participation by AAs in lung cancer clinical trials are needed to integrate, and leverage, transcriptomic differences with other clinical information to maximize therapeutic benefit in both AAs and EAs. .

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Section: Discussionmentioning

confidence: 99%

Comparative Transcriptome Profiling Reveals Coding and Noncoding RNA Differences in NSCLC from African Americans and European Americans

Mitchell

Zingone

Toulabi

et al. 2017

Clinical Cancer Research

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“…Other studies further revealed that BA induces apoptotic cell death in human cancers, including head and neck, colon, breast, prostate, ovarian, and cervical cancers, by triggering the mitochondrial apoptotic pathway, but showed that normal cells and tissue are relatively resistant to BA [14]. Recently, our group further demonstrated that SYK023, a synthetic derivative of BA, attenuates lung-cancer growth and malignancy by increasing ER stress [15]. However, the mechanisms underlying the specific targets of BA during ER stress remain elusive.…”

Section: Introductionmentioning

confidence: 96%

Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma

Hsu

Yang

et al. 2020

Cancers

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Patients with glioblastoma are at high risk of local recurrences after initial treatment with standard therapy, and recurrent tumor cells appear to be resistant to first-line drug temozolomide. Thus, finding an effective second-line agent for treating primary and recurrent glioblastomas is critical. Betulinic acid (BA), a natural product of plant origin, can cross the blood–brain barrier. Here, we investigated the antitumor effects of BA on typical glioblastoma cell lines and primary glioblastoma cells from patients, as well as corresponding temozolomide-resistant cells. Our findings verified that BA significantly reduced growth in all examined cells. Furthermore, gene-expression array analysis showed that the unfolded-protein response was significantly affected by BA. Moreover, BA treatment increased activation of the protein kinase RNA-like endoplasmic reticulum kinase (PERK)/C/EBP homologous protein (CHOP) apoptotic pathway, and reduced specificity protein 1 (Sp1) expression. However, Sp1 overexpression reversed the observed cell-growth inhibition and PERK/CHOP signaling activation induced by BA. Because temozolomide-resistant cells exhibited significantly increased Sp1 expression, we concluded that Sp1-mediated PERK/CHOP signaling inhibition protects glioblastoma against cancer therapies; hence, BA treatment targeting this pathway can be considered as an effective therapeutic strategy to overcome such chemoresistance and tumor relapse.

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“…For a long time, 30-carbon terpenoids derivatives were mistakenly considered to be biologically inactive. Although several studies conducted in past years have suggested that triterpenoids possess various activities, including hepatoprotective, cytotoxic, anti-inflammatory as well as anti-cancer [6,7]. This resulted in a constantly growing eagerness to elucidate their potential.…”

Section: Introductionmentioning

confidence: 99%

Betulin and betulinic acid in cancer research

Hordyjewska¹,

Ostapiuk²,

Horecka³

2018

J Pre Clin Clin Res.

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Introduction. Terpenes are the largest known class of organic compounds, widely distributed in plants. They are grouped considering the number of isoprene units in their structure; hence, the group consisting of 30 carbon atoms is called triterpenes. These compounds have a wide range of biological features. Objective. The aim of this review was to comprehensively discuss the role of betulin and betulinic acid as potent anticancer agents, including various studies determining their efficiency in cancer treatment and enumerating the types of cancer susceptible to this kind of therapy. State of knowledge. Betulin is a naturally occurring lupane-type pentacyclic triterpene, wildly distributed in plants, especially Betulinaceae. One of its derivatives, formed by oxidation, is betulinic acid. Both compounds are abundantly present in the outer bark of white birch, with betulin forming up to 34% its dry mass and are known for their valuable biological properties, including anti-cancer effect. By inducing the internal apoptosis pathway in cancer cells while sparing normal cells, they are a great help in the treatment of most malignancies, alone or in combination with radio-or chemotherapy. Summary. Compounds that have a direct effect on mitochondria are promising experimental anticancer drugs, since they are able to cause cell death in conditions in which conventional therapies, including chemotherapeutics, usually fail. Therefore, mitochondrial targeting agents such as betulin and betulinic acid are a promise of a new therapeutic strategy for the treatment of human tumours.

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A novel derivative of betulinic acid, SYK023, suppresses lung cancer growth and malignancy

Cited by 27 publications

References 59 publications

Comparative Transcriptome Profiling Reveals Coding and Noncoding RNA Differences in NSCLC from African Americans and European Americans

Comparative Transcriptome Profiling Reveals Coding and Noncoding RNA Differences in NSCLC from African Americans and European Americans

Betulinic Acid-Mediated Tuning of PERK/CHOP Signaling by Sp1 Inhibition as a Novel Therapeutic Strategy for Glioblastoma

Betulin and betulinic acid in cancer research

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