Gambogic acid induces apoptosis and inhibits colorectal tumor growth<i>via</i>mitochondrial pathways

Huang, Guangming; Sun, Yu; Wan, Xin; Li, Chunbo

doi:10.3748/wjg.v21.i20.6194

Cited by 39 publications

(25 citation statements)

References 56 publications

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“…GBA potently inhibits cancer cell proliferation in vitro and in mouse xenograft models (37)(38)(39)(40)(41). Although GBA is reported to have multiple effects in cancer cells (42,43), recent studies have ascribed some of GBA's antitumor activity to its binding to Hsp90 (44,45).…”

Section: Significancementioning

confidence: 99%

Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90β

Yim

Prince

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Because of their importance in maintaining protein homeostasis, molecular chaperones, including heat-shock protein 90 (Hsp90), represent attractive drug targets. Although a number of Hsp90 inhibitors are in preclinical/clinical development, none strongly differentiate between constitutively expressed Hsp90β and stress-induced Hsp90α, the two cytosolic paralogs of this molecular chaperone. Thus, the importance of inhibiting one or the other paralog in different disease states remains unknown. We show that the natural product, gambogic acid (GBA), binds selectively to a site in the middle domain of Hsp90β, identifying GBA as an Hsp90β-specific Hsp90 inhibitor. Furthermore, using computational and medicinal chemistry, we identified a GBA analog, referred to as DAP-19, which binds potently and selectively to Hsp90β. Because of its unprecedented selectivity for Hsp90β among all Hsp90 paralogs, GBA thus provides a new chemical tool to study the unique biological role of this abundantly expressed molecular chaperone in health and disease.

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Section: Significancementioning

confidence: 99%

Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90β

Yim

Prince

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…This motif is further decorated via A-ring substitutions and peripheral oxidations to produce a variety of natural products with a broad range of bioactivities (11). Gambogic acid (GBA), the archetype of this family, potently inhibits cancer cell proliferation in solid tumors (13)(14)(15)(16)(17) and hematological malignancies (18) and has entered clinical trials in China for patients with non-small-cell lung, colon, and renal cancers (19). In addition, the potent cytotoxicity of several CGXs at low micromolar concentrations has been well documented (20)(21)(22)(23).…”

mentioning

confidence: 99%

Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity

Morrisey

et al. 2017

Antimicrob Agents Chemother

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Caged Garcinia xanthones (CGXs) constitute a family of natural products that are produced by tropical/subtropical trees of the genus Garcinia. CGXs have a unique chemical architecture, defined by the presence of a caged scaffold at the C ring of a xanthone moiety, and exhibit a broad range of biological activities. Here we show that synthetic CGXs exhibit antimalarial activity against Plasmodium falciparum, the causative parasite of human malaria, at the intraerythrocytic stages. Their activity can be substantially improved by attaching a triphenylphosphonium group at the A ring of the caged xanthone. Specifically, CR135 and CR142 were found to be highly effective antimalarial inhibitors, with 50% effective concentrations as low as ϳ10 nM. CGXs affect malaria parasites at multiple intraerythrocytic stages, with mature stages (trophozoites and schizonts) being more vulnerable than immature rings. Within hours of CGX treatment, malaria parasites display distinct morphological changes, significant reduction of parasitemia (the percentage of infected red blood cells), and aberrant mitochondrial fragmentation. CGXs do not, however, target the mitochondrial electron transport chain, the target of the drug atovaquone and several preclinical candidates. CGXs are cytotoxic to human HEK293 cells at the low micromolar level, which results in a therapeutic window of around 150-fold for the lead compounds. In summary, we show that CGXs are potent antimalarial compounds with structures distinct from those of previously reported antimalarial inhibitors. Our results highlight the potential to further develop Garcinia natural product derivatives as novel antimalarial agents.

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“…In this study, a rat model (Crl:NIH‐ Foxn1 rnu , Charles River) was used to test a new antitumor regimen (AGCH: cisplatin, adriamycin, herceptin, and gemcitabine) to treat CRC. Each rat was inoculated subcutaneously at the rear right flank with HT‐29 colon cancer cells (1 × 10 6 ) in 0.1 mL of PBS . The tumor size served as the primary efficacy indicator.…”

Section: Resultsmentioning

confidence: 99%

Harnessing an Artificial Intelligence Platform to Dynamically Individualize Combination Therapy for Treating Colorectal Carcinoma in a Rat Model

Chang

et al. 2019

Advanced Therapeutics

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Designing multi-drug regimens often involves target-and synergy prediction-based drug selection, and subsequent dose escalation to achieve the maximum tolerated dose (MTD) of each drug. This approach may improve efficacy, but not the optimal efficacy and often substantially increases toxicity. Drug interactions depend on many pathways in the omics networks and further complicate the design process. The virtually infinite drug-dose parameter space cannot be reconciled using conventional approaches, which are largely based on prediction. This barrier at least partially accounts for the low response rates that are observed with conventional mono-and combinatorial chemotherapy. A combination of nonstandard therapies for colorectal cancer (AGCH: adriamycin, gemcitabine, cisplatin, and herceptin) at ¼ MTD is used to treat the rats, the tumor response rates varied in a wide range. Some of the tumor response rates are close to that of control group. This work harnesses an artificial intelligence (AI) platform that is mechanism free and can dynamically optimize combinatorial therapy in rats. The individually optimized AGCH regimen reveal starkly different drug-dose parameters, which can converge each rat toward the same and low tumor response rate. Importantly, this AI-based drug-dose optimization technology is an actionable platform, which can achieve N-of-1 therapy.

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Gambogic acid induces apoptosis and inhibits colorectal tumor growthviamitochondrial pathways

Abstract: GA inhibits HT-29 proliferation via induction of apoptosis. The anti-cancer effects are likely mediated by death receptor (extrinsic) and mitochondrial (intrinsic) pathways.

Cited by 39 publications

References 56 publications

Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90β

Gambogic acid identifies an isoform-specific druggable pocket in the middle domain of Hsp90β

Caged Garcinia Xanthones, a Novel Chemical Scaffold with Potent Antimalarial Activity

Harnessing an Artificial Intelligence Platform to Dynamically Individualize Combination Therapy for Treating Colorectal Carcinoma in a Rat Model

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