ASR488, a novel small molecule, activates an mRNA binding protein, CPEB1, and inhibits the growth of bladder cancer

Tyagi, Ashish; Kolluru, Venkatesh; Chandrasekaran, Balaji; Saran, Uttara; Sharma, Arun; Ankem, Murali K.; Damodaran, Chendil

doi:10.3892/ol.2020.11593

Cited by 5 publications

(4 citation statements)

References 30 publications

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“…For instance, the 2-thiophene ester-linked derivative of WA, ASR488, selectively inhibited bladder cancer cells while showing no toxicity to normal cells. 189 Furthermore, a range of IC 50 values for withanolides, as reported by Zhang et al, suggests the existence of various compounds within this class with potential anti-cancer activity, warranting further exploration and development. 190 Notably, the ability of another WA derivate, ASR490, to inhibit the growth of colon cancer cell lines and xenotransplanted tumors without causing systemic toxicity is encouraging.…”

Section: Limitations Of Wa As a Potential Anti-cancer Candidate And C...mentioning

confidence: 90%

Withaferin A: A Dietary Supplement with Promising Potential as an Anti-Tumor Therapeutic for Cancer Treatment - Pharmacology and Mechanisms

Xing,

Su,

et al. 2023

DDDT

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Cancer, as the leading cause of death worldwide, poses a serious threat to human health, making the development of effective tumor treatments a significant challenge. Natural products continue to serve as crucial resources for drug discovery. Among them, Withaferin A (WA), the most active phytocompound extracted from the renowned dietary supplement Withania somnifera (L.) Dunal, exhibits remarkable anti-tumor efficacy. In this manuscript, we aim to comprehensively summarize the pharmacological characteristics of WA as a potential anti-tumor drug candidate, with the objective of contributing to its further development and the discovery of prospective drugs. Through an extensive review of literature from PubMed, Science Direct, and Web of Science, we have gathered substantial evidence showcasing WA’s significant anti-tumor effects against a wide range of cancers in both in vitro and in vivo studies. Mechanistically, WA exerts its anti-tumor influence by inducing cell cycle arrest, apoptosis, autophagy, and ferroptosis. Additionally, it inhibits cell proliferation, cancer stem cells, tumor metastasis, and also suppresses epithelial-mesenchymal transition (EMT) and angiogenesis. Several studies have identified direct target proteins of WA, such as vimentin, Hsp90, annexin II and mFAM72A, while BCR-ABL, Mortalin (mtHsp70), Nrf2, and c-MYB are potential targets of WA. Notwithstanding its remarkable anti-tumor efficacy, there are some limitations associated with WA, including potential toxicity and poor oral bioavailability, which need to be addressed when considering it as an anti-tumor candidate agent. Nevertheless, I given its promising anti-tumor attributes, WA remains an encouraging candidate for future drug development. Unveiling the exact target and comprehensive mechanism of WA’s action represents a crucial research direction to pursue in the future.

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Section: Limitations Of Wa As a Potential Anti-cancer Candidate And C...mentioning

confidence: 90%

Withaferin A: A Dietary Supplement with Promising Potential as an Anti-Tumor Therapeutic for Cancer Treatment - Pharmacology and Mechanisms

Xing,

Su,

et al. 2023

DDDT

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“…As previously described [ 21 ], apoptosis was detected using the annexin V-fluorescein isothiocyanate (FITC) versus propidium iodide (PI) assay (FITC Annexin V Apoptosis Detection Kit I, BD Pharminogen).…”

Section: Methodsmentioning

confidence: 99%

Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC)

Chandrasekaran

Tapadar

et al. 2023

Cancers

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Background: Epigenetic modification influences androgen receptor (AR) activation, often resulting in prostate cancer (PCa) development and progression. Silencing histone-modifying enzymes (histone deacetylases-HDACs) either genetically or pharmacologically suppresses PCa proliferation in preclinical models of PCa; however, results from clinical studies were not encouraging. Similarly, PCa patients eventually become resistant to androgen ablation therapy (ADT). Our goal is to develop dual-acting small molecules comprising antiandrogen and HDAC-inhibiting moieties that may overcome the resistance of ADT and effectively suppress the growth of castration-resistant prostate cancer (CRPC). Methods: Several rationally designed antiandrogen-equipped HDAC inhibitors (HDACi) were synthesized, and their efficacy on CRPC growth was examined both in vitro and in vivo. Results: While screening our newly developed small molecules, we observed that SBI-46 significantly inhibited the proliferation of AR+ CRPC cells but not AR- CRPC and normal immortalized prostate epithelial cells (RWPE1) or normal kidney cells (HEK-293 and VERO). Molecular analysis confirmed that SBI-46 downregulated the expressions of both AR+ and AR-splice variants (AR-SVs) in CRPC cells. Further studies revealed the downregulation of AR downstream (PSA) events in CRPC cells. The oral administration of SBI-46 abrogated the growth of C4-2B and 22Rv1 CRPC xenograft tumors that express AR or both AR and AR-SV in xenotransplanted nude mice models. Further, immunohistochemical analysis confirmed that SBI-46 inhibits AR signaling in xenografted tumor tissues. Conclusion: These results demonstrate that SBI-46 is a potent agent that inhibits preclinical models of CRPC by downregulating the expressions of both AR and AR-SV. Furthermore, these results suggest that SBI-46 may be a potent compound for treating CRPC.

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“…This effort has led to several novel analogs with varying degrees of anti-cancer potency (unpublished results). Two of the C4-ester linked compounds reported so far, ASR490 ( 116 ) and ASR488 ( 117 ) ( Figure 14 ), have demonstrated promising therapeutic potential against colorectal and bladder cancers, respectively [ 51 , 112 ]. The 2-pyridyl ester-linked ASR490 ( 116 ) showed the robust growth inhibition of HCT116 and SW620 colon cancer cell lines via the downregulation of the Notch1 signaling pathway.…”

Section: Withanolides As Anti-cancer Agentsmentioning

confidence: 99%

“…Further, it effectively inhibited tumor growth in control (pCMV/HCT116) and Notch1/HCT116 xenotransplanted mice without any apparent systemic toxicity. The 2-thiophene ester-linked analog ASR488 ( 117 ) was selectively toxic to bladder cancer cells, while it was relatively non-toxic to normal cells [ 112 ]. These reports attest to the therapeutic potential of appropriately designed WA analogs.…”

Section: Withanolides As Anti-cancer Agentsmentioning

confidence: 99%

Recent Advances in the Chemistry and Therapeutic Evaluation of Naturally Occurring and Synthetic Withanolides

et al. 2022

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Natural products are a major source of biologically active compounds that make promising lead molecules for developing efficacious drug-like molecules. Natural withanolides are found in many flora and fauna, including plants, algae, and corals, that traditionally have shown multiple health benefits and are known for their anti-cancer, anti-inflammatory, anti-bacterial, anti-leishmaniasis, and many other medicinal properties. Structures of these withanolides possess a few reactive sites that can be exploited to design and synthesize more potent and safe analogs. In this review, we discuss the literature evidence related to the medicinal implications, particularly anticancer properties of natural withanolides and their synthetic analogs, and provide perspectives on the translational potential of these promising compounds.

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ASR488, a novel small molecule, activates an mRNA binding protein, CPEB1, and inhibits the growth of bladder cancer

Cited by 5 publications

References 30 publications

Withaferin A: A Dietary Supplement with Promising Potential as an Anti-Tumor Therapeutic for Cancer Treatment - Pharmacology and Mechanisms

Withaferin A: A Dietary Supplement with Promising Potential as an Anti-Tumor Therapeutic for Cancer Treatment - Pharmacology and Mechanisms

Antiandrogen-Equipped Histone Deacetylase Inhibitors Selectively Inhibit Androgen Receptor (AR) and AR-Splice Variant (AR-SV) in Castration-Resistant Prostate Cancer (CRPC)

Recent Advances in the Chemistry and Therapeutic Evaluation of Naturally Occurring and Synthetic Withanolides

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