Potency and pharmacokinetics of broad spectrum and isoform-specific p110<b>γ</b>and<b>δ</b>inhibitors in cancers

Setti, Aravind; Kumar, Manjeet; Babu, Kavita; Rasagna, A; Prasanna, M.; Devi, T. Anjana; Pawar, Sunil

doi:10.3109/10799893.2014.1003658

Cited by 6 publications

(5 citation statements)

References 45 publications

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“…To this end, we took advantage of inhibitors that have been designed to target PI3K isoforms individually or in combination ( Table 1 ). Specifically, we pretreated neutrophils with 10 μM HS-173, a specific PI3Kα inhibitor, 20 μM of the PI3Kα/PI3Kδ-selective inhibitor GDC-0941 (also called Pictilisib), 1 μM of the PI3Kδ-selective inhibitors IC-87114 and PIK-294, or 100 μM of the PI3Kβ-selective inhibitor TGX-221 ( Juss et al., 2012 ; Sarker et al., 2015 ; Setti et al., 2016 ; Zillikens et al., 2021 ) and monitored apoptosis over the course of 24 hours in the presence and absence of LVS.…”

Section: Resultsmentioning

confidence: 99%

Neutrophil Survival Signaling During Francisella tularensis Infection

Kinkead

Krysa

Allen

2022

Front. Cell. Infect. Microbiol.

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Neutrophils are the most abundant and shortest-lived leukocytes in humans and tight regulation of neutrophil turnover via constitutive apoptosis is essential for control of infection and resolution of inflammation. Accordingly, aberrant neutrophil turnover is hallmark of many disease states. We have shown in previous work that the intracellular bacterial pathogen Francisella tularensis markedly prolongs human neutrophil lifespan. This is achieved, in part, by changes in neutrophil gene expression. Still unknown is the contribution of major neutrophil pro-survival signaling cascades to this process. The objective of this study was to interrogate the contributions of ERK and p38 MAP kinase, Class I phosphoinositide 3-kinases (PI3K), AKT, and NF-κB to neutrophil survival in our system. We demonstrate that both ERK2 and p38α were activated in F. tularensis-infected neutrophils, but only p38α MAPK was required for delayed apoptosis and the rate of cell death in the absence of infection was unchanged. Apoptosis of both infected and uninfected neutrophils was markedly accelerated by the pan-PI3K inhibitor LY2094002, but AKT phosphorylation was not induced, and neutrophil death was not enhanced by AKT inhibitors. In addition, isoform specific and selective inhibitors revealed a unique role for PI3Kα in neutrophil survival after infection, whereas only simultaneous inhibition of PI3Kα and PI3kδ accelerated death of the uninfected controls. Finally, we show that inhibition of NF-κB triggered rapid death of neutrophil after infection. Thus, we defined roles for p38α, PI3Kα and NF-κB delayed apoptosis of F. tularensis-infected cells and advanced understanding of Class IA PI3K isoform activity in human neutrophil survival.

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Section: Resultsmentioning

confidence: 99%

Neutrophil Survival Signaling During Francisella tularensis Infection

Kinkead

Krysa

Allen

2022

Front. Cell. Infect. Microbiol.

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“…GNE-490 is effective against mouse xenograft models of breast and prostate cancers [35]. In contrast, drug resistance was found for two PI3K inhibitors (see Figure 6): PIK-294, an inhibitor that is somewhat selective for the PI3K catalytic subunit p110δ [36], and to a lesser extent, BYL-719, which is selective for the p110α subunit [37]. The result for BYL- 719 is unexpected, given the sensitivity of the cells to GNE-490, another p110α inhibitor.…”

Section: Pi3k and Akt1 Inhibitorsmentioning

confidence: 99%

Drug Responses in Plexiform Neurofibroma Type I (PNF1) Cell Lines Using High-Throughput Data and Combined Effectiveness and Potency

Zamora,

Altay,

Santamaria

et al. 2023

Cancers

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Background: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by heterozygous germline NF1 gene mutations that predispose patients to developing plexiform neurofibromas, which are benign but often disfiguring tumors of the peripheral nerve sheath induced by loss of heterozygosity at the NF1 locus. These can progress to malignant peripheral nerve sheath tumors (MPNSTs). There are no approved drug treatments for adults with NF1-related inoperable plexiform neurofibromas, and only one drug (selumetinib), which is an FDA-approved targeted therapy for the treatment of symptomatic pediatric plexiform neurofibromas, highlighting the need for additional drug screening and development. In high-throughput screening, the effectiveness of drugs against cell lines is often assessed by measuring in vitro potency (AC50) or the area under the curve (AUC). However, the variability of dose–response curves across drugs and cell lines and the frequency of partial effectiveness suggest that these measures alone fail to provide a full picture of overall efficacy. Methods: Using concentration–response data, we combined response effectiveness (EFF) and potency (AC50) into (a) a score characterizing the effect of a compound on a single cell line, S = log[EFF/AC50], and (b) a relative score, ΔS, characterizing the relative difference between a reference (e.g., non-tumor) and test (tumor) cell line. ΔS was applied to data from high-throughput screening (HTS) of a drug panel tested on NF1−/− tumor cells, using immortalized non-tumor NF1+/− cells as a reference. Results: We identified drugs with sensitivity, targeting expected pathways, such as MAPK-ERK and PI3K-AKT, as well as serotonin-related targets, among others. The ΔS technique used here, in tandem with a supplemental ΔS web tool, simplifies HTS analysis and may provide a springboard for further investigations into drug response in NF1-related cancers. The tool may also prove useful for drug development in a variety of other cancers.

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“…Although sorafenib can inhibit the growth of tumors in situ, it mobilizes a large number of macrophages into the blood and promotes the activation of macrophages to M2 type, resulting in great trouble for the treatment and prognosis of liver cancer (Wei et al., 2017). While TG100-115 is an exclusive PI3Kγ inhibitor, which can improve the progression of various types of tumors (including liver cancer, lymphoma and breast cancer) by reversing the phenotype of TAMs, inhibiting tumor angiogenesis, enhancing the recruitment of cytotoxic T lymphocytes, and relieving immunosuppression (Setti et al., 2016). Thus, the combination of sorafenib and TG100-115 may produce significant synergistic effects and improve antitumor efficacy.…”

Section: Introductionmentioning

confidence: 99%

Sorafenib-loaded hydroxyethyl starch-TG100-115 micelles for the treatment of liver cancer based on synergistic treatment

Zhao

2019

Drug Delivery

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Tumor microenvironment is closely related to the occurrence and development of liver cancer. Tumorassociated macrophages (TAMs) are an important part of tumor microenvironment promoting tumor deterioration and metastasis by inhibiting immune cells. Previous studies showed that PI3Kc inhibitor could reverse the phenotype of TAMs, relieve immunosuppression and sensitize chemotherapy drugs, suggesting that the combination of PI3Kc inhibitor and chemotherapeutics is likely to bring new breakthroughs in the treatment of liver cancer. Based on it, this paper builds HES-TG100-115-CDM-PEG micelles with tumor microenvironment responsiveness that simultaneously loaded sorafenib and TG100-115 to synergistically treat liver cancer. Pharmacokinetic study showed that the prepared micelles had longer half-life than that of the free drug solutions, which was favorable for high propensity of extravasation through tumor vascular fenestrations. Under low pH and high a-amylasereductive conditions, micelles could depolymerize quickly due to the sensitivity of bonds and enhance significantly cytotoxic activity against Hep-3B liver cancer cell. Additionally, micelles demonstrated higher levels of antitumor efficiency and better tolerance against nude mouse with Hep-3B cell than the free drug solutions. These findings reveal that HES-TG100-115-CDM-PEG micelles are a promising drug delivery system in clinical comprehensive therapy of liver cancer.

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Potency and pharmacokinetics of broad spectrum and isoform-specific p110γandδinhibitors in cancers

Cited by 6 publications

References 45 publications

Neutrophil Survival Signaling During Francisella tularensis Infection

Neutrophil Survival Signaling During Francisella tularensis Infection

Drug Responses in Plexiform Neurofibroma Type I (PNF1) Cell Lines Using High-Throughput Data and Combined Effectiveness and Potency

Sorafenib-loaded hydroxyethyl starch-TG100-115 micelles for the treatment of liver cancer based on synergistic treatment

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