VERU-111 suppresses tumor growth and metastatic phenotypes of cervical cancer cells through the activation of p53 signaling pathway

Kashyap, Vivek K.; Dan, Nirnoy; Chauhan, Neeraj; Wang, Qinghui; Setua, Saini; Nagesh, Prashanth K.B.; Malik, Shabnam; Batra, Vivek; Yallapu, Murali M.; Miller, Duane D.; Li, Wei; Hafeez, Bilal Bin; Jaggi, Meena; Chauhan, Subhash C.

doi:10.1016/j.canlet.2019.11.035

Cited by 15 publications

(15 citation statements)

References 52 publications

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“…Although combinations of BRAF inhibitor with MEK or ERK inhibitors benefit Vem-resistant patients (Atefi et al, 2011;Gadiot et al, 2013;Pulkkinen et al, 2020), half of the patients still gain resistance after 6-8 months. Intriguingly, some tubulin destabilizing agents reported previously by us targeting the colchicine-binding site showed promise to overcome Vemresistance, paclitaxel-resistance in melanoma, breast cancer, lung cancer, prostate cancer, cervical cancer et al (Wang et al, 2014;Guan et al, 2017;Arnst et al, 2018;Deng et al, 2020;Kashyap et al, 2020;Mahmud et al, 2020). In our previous studies, we have demonstrated that a tool tubulin inhibitor, ABI-274, showed strong synergistic efficacy in a Vem-resistant xenograft mouse model (Wang et al, 2014).…”

Section: Introductionmentioning

confidence: 83%

“…From Vem-Sensitive A375 Cells A375 cells are one of the most widely used and representative V600E mutant melanoma cells, and we have previously reported the anti-tumor efficiency of VERU-111 in many cancer types (Kashyap et al, 2019;Deng et al, 2020;Kashyap et al, 2020;Mahmud et al, 2020) as well as the synergy of Vem in combination with ABI-274 in A375 Vem-resistant melanoma cells (Wang et al, 2014). Herein, we investigate whether the combination of VERU-111 (ABI-274 derivative) with Vem can also overcome Vemresistance in A375.…”

Section: Development Of Vem-resistant Vr1 Cellsmentioning

confidence: 99%

“…ABI-274 is a tool compound developed in our lab as a potent tubulin inhibitor that binds to the colchicine binding site (Chen et al, 2010;Wang et al, 2018). Further structural optimization from ABI-274 led to VERU-111 (Figure 1A), which is orally available and much more potent and less toxic in several types of tumor models, including prostate cancer, melanoma, breast cancer, lung cancer, and pancreatic cancer (Chen et al, 2012;Deng et al, 2020;Kashyap et al, 2020;Mahmud et al, 2020 (Chen et al, 2020). VERU-111 has now been under Phase 1b/2 clinical trials for men with metastatic castration and androgen-blocking agent resistant prostate cancer (ClinicalTrials.gov Identifier: NCT03752099) and holds great promise to become an oral tubulin inhibitor targeting the colchicine binding site.…”

Section: Introductionmentioning

confidence: 99%

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The Tubulin Inhibitor VERU-111 in Combination With Vemurafenib Provides an Effective Treatment of Vemurafenib-Resistant A375 Melanoma

et al. 2021

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Melanoma is one of the deadliest skin cancers having a five-year survival rate around 15–20%. An overactivated MAPK/AKT pathway is well-established in BRAF mutant melanoma. Vemurafenib (Vem) was the first FDA-approved BRAF inhibitor and gained great clinical success in treating late-stage melanoma. However, most patients develop acquired resistance to Vem within 6–9 months. Therefore, developing a new treatment strategy to overcome Vem-resistance is highly significant. Our previous study reported that the combination of a tubulin inhibitor ABI-274 with Vem showed a significant synergistic effect to sensitize Vem-resistant melanoma both in vitro and in vivo. In the present study, we unveiled that VERU-111, an orally bioavailable inhibitor of α and β tubulin that is under clinical development, is highly potent against Vem-resistant melanoma cells. The combination of Vem and VERU-111 resulted in a dramatically enhanced inhibitory effect on cancer cells in vitro and Vem-resistant melanoma tumor growth in vivo compared with single-agent treatment. Further molecular signaling analyses demonstrated that in addition to ERK/AKT pathway, Skp2 E3 ligase also plays a critical role in Vem-resistant mechanisms. Knockout of Skp2 diminished oncogene AKT expression and contributed to the synergistic inhibitory effect of Vem and VERU-111. Our results indicate a treatment combination of VERU-111 and Vem holds a great promise to overcome Vem-resistance for melanoma patients harboring BRAF (V600E) mutation.

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Section: Introductionmentioning

confidence: 83%

Section: Development Of Vem-resistant Vr1 Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Tubulin Inhibitor VERU-111 in Combination With Vemurafenib Provides an Effective Treatment of Vemurafenib-Resistant A375 Melanoma

et al. 2021

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“…Under normal conditions, p53 is a short-lived protein that shuttles between the nucleus and the cytoplasm in a cell cycle-speci c manner [31] . Relocation of p53 to the nucleus in response to cellular stress is a contributor to the inhibition of the growth of cancer cells [42] .…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have proven that p53 function is tightly regulated by its cellular localization, and p53 is synthesized in the cytoplasm while exerting its transcriptional effect on downstream targets responding to cellular stress only after being transported to the nucleus [31] . The results from western blot analysis and immuno uorescence staining showed that in the BZML-treated A549/Taxol cells, the expression of p53 increased only slightly in the cytoplasm but was signi cantly upregulated in a time-dependent manner in the nucleus ( Fig.…”

Section: Bzml Activated P53 Through Multiple Mechanisms In the A549/tmentioning

confidence: 99%

Survivin Suppression Strengthens BZML-induced Mitotic Catastrophe to Overcome Multidrug Resistance by Removing Senescent A549/Taxol Cells

Bai¹,

Zhou²,

Ye³

et al. 2020

Preprint

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Background: Mitotic catastrophe (MC) of cancer cells induced by BZML, a novel colchicine-binding site inhibitor, exerts a significant advantage in overcoming multidrug resistance (MDR) in NSCLC. However, the long cellular death process resulting from MC is not beneficial for anticancer treatment. Here, we study the mechanisms underlying MC occurrence and development to promote the development of anticancer therapies based on drug-induced MC.Methods: Cellular senescence was confirmed by morphological features, SA-β-Gal and C12FDG staining. Cell cycle analysis and Hoechst 33342 staining were used to detect MC. Relevant signal transduction pathways and protein location were detected by qRT-PCR, westren blot and immunofluorescence. The half-life of proteins was evaluated using the protein synthesis inhibitor cycloheximide. Flow cytometry, MTT assay, crystal violet staining, Hoechst 33342 staining and cell division detection were performed to determine the effects of BZML and/or YM155 on cell fate. Results: We found that BZML induced p53-dependent cellular senescence in A549/Taxol cells, but not in A549, H1299 and MDA-MB-231 cells. Interestingly, BZML-induced senescence was a secondary effect of MC. In addition, the destruction of the protein-degradation system induced by BZML contributed not only to an increase in p53 protein but also to the accumulation of survivin in the nucleus of A549/Taxol cells. However, in A549 cells, the overexpression of survivin had no effect on apoptosis resistance against BZML and failed to promote BZML-induced MC. The inhibition of survivin did not prevent MC occurrence. Unexpectedly, targeting survivin with YM155 accelerated the death of the MC cells by eliminating senescent cells and strengthening the efficiency of BZML in overcoming the MDR of A549/Taxol cells.Conclusions: Our data suggest that nuclear accumulation of survivin can delay cellular death during MC by promoting the survival of senescent BZML-treated A549/Taxol cells. Further, depending on the dose sequence, combination therapy with YM155 to inhibit survivin might be a new strategy for potentiating BZML-induced MC to overcome MDR during cancer treatment.

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HPV E6 promotes cell proliferation of cervical cancer cell by accelerating accumulation of RBM15 dependently of autophagy inhibition

Nie

Tang

et al. 2023

Cell Biology International

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The mechanism of m6A modification in HPV‐related cervical cancer remains unclear. This study explored the role of methyltransferase components in HPV‐related cervical cancer and the mechanism. The levels of methyltransferase components and autophagy, ubiquitylation of RBM15 protein and the co‐localization of lysosomal markers LAMP2A and RBM15 were measured. CCK‐8 assay, flow cytometry, clone formation experiment and immunofluorescence assay were conducted to measure cell proliferation. The mouse tumor model was developed to study the cell growth in vivo. The binding of RBM15 to c‐myc mRNA and m6A modifcation of c‐myc mRNA were analyzed. The expressions of METTL3, RBM15 and WTAP were higher in HPV‐positive cervical cancer cell lines than those in HPV‐negative cells, especially RBM15. HPV‐E6 knock‐down inhibited the expression of RBM15 protein and promoted its degradation, but couldn't change its mRNA level. Autophagy inhibitor and proteasome inhibitor could reverse those effects. HPV‐E6 siRNA could not enhance ubiquitylation modification of RBM15, but could enhance autophagy and the co‐localization of RBM15 and LAMP2A. RBM15 overexpression could enhance cell proliferation, block the inhibitory effects of HPV‐E6 siRNA on cell growth, and these effects could be reserved by cycloeucine. RBM15 could bind to c‐myc mRNA, resulting in an increase to m6A level and protein expression of c‐myc, which could be blocked by cycloeucine. HPV‐E6 can downregulate autophagy, inhibit the degradation of RBM15 protein, induce the accumulation of intracellular RBM15, and increase the m6A modification on c‐myc mRNA, resulting in an increase of c‐myc protein and a growth promotion for cervical cancer cells.

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VERU-111 suppresses tumor growth and metastatic phenotypes of cervical cancer cells through the activation of p53 signaling pathway

Cited by 15 publications

References 52 publications

The Tubulin Inhibitor VERU-111 in Combination With Vemurafenib Provides an Effective Treatment of Vemurafenib-Resistant A375 Melanoma

The Tubulin Inhibitor VERU-111 in Combination With Vemurafenib Provides an Effective Treatment of Vemurafenib-Resistant A375 Melanoma

Survivin Suppression Strengthens BZML-induced Mitotic Catastrophe to Overcome Multidrug Resistance by Removing Senescent A549/Taxol Cells

HPV E6 promotes cell proliferation of cervical cancer cell by accelerating accumulation of RBM15 dependently of autophagy inhibition

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