Aberrant activation of the PI3K/Akt signalling pathway, a major driving force of diverse cellular processes has been implicated in tumour development and progression. Here, we report that astaxanthin (AXT), a potent antioxidant ketocarotenoid prevents cancer hallmarks by inhibiting PI3K/Akt and the associated downstream NF‐κB and STAT‐3 signalling pathways in SCC131 and SCC4 oral cancer cells as well as in the hamster buccal pouch carcinogenesis model. Using small molecule inhibitors of NF‐κB, STAT‐3 and PI3K and by overexpression of PI3K, we provide evidence to show that AXT inhibits NF‐κB and STAT‐3 signalling and cancer hallmarks by restraining the kinase activity of PI3K/Akt. Additionally, AXT downregulated the noncoding RNAs (ncRNAs), miR‐21 and HOTAIR that influence PI3K/Akt signalling emphasising its modulatory effects on epigenetic regulation. Ethyl cellulose‐based AXT nanoparticles showed greater chemotherapeutic efficacy in the hamster oral carcinogenesis model compared to native AXT. We suggest that AXT prevents cell proliferation, apoptosis evasion, invasion and angiogenesis by intercepting the crosstalk between the PI3K/Akt, NF‐κB and STAT‐3 signalling circuits both in vitro and in vivo. Astaxanthin that abrogates the PI3K/Akt signalling axis, a central hub that orchestrates acquisition of cancer hallmarks is a promising candidate for anticancer drug development.
Nimbolide, a major limonoid constituent of Azadirachta
indica, commonly known as neem, has attracted increasing
research attention owing to its wide spectrum of pharmacological properties,
predominantly anticancer activity. Nimbolide is reported to exert
potent antiproliferative effects on a myriad cancer cell lines and
chemotherapeutic efficacy in preclinical animal tumor models. The
potentiality of nimbolide to circumvent multidrug resistance and aid
in targeted protein degradation broaden its utility in enhancing therapeutic
modalities and outcome. Accumulating evidence indicates that nimbolide
prevents the acquisition of cancer hallmarks such as sustained proliferation,
apoptosis evasion, invasion, angiogenesis, metastasis, and inflammation
by modulating kinase-driven oncogenic signaling networks. Nimbolide
has been demonstrated to abrogate aberrant activation of cellular
signaling by influencing the subcellular localization of transcription
factors and phosphorylation of kinases in addition to influencing
the epigenome. Nimbolide, with its ever-expanding repertoire of molecular
targets, is a valuable addition to the anticancer drug arsenal.
Background & Objectives:
There is growing evidence to implicate the insulin/IGF-1R/PI3K/Akt signaling cascade in breast cancer development and the central role of aldose reductase (AR) in mediating the crosstalk between this pathway and angiogenesis. The current study was designed to investigate whether nimbolide, a neem limonoid, targets this oncogenic signaling network to prevent angiogenesis in breast cancer.
Methods:
Breast cancer cells (MCF-7, MDA-MB-231), EAhy926 endothelial cells, MDA-MB-231 xenografted nude mice, and tumour tissues from breast cancer patients were used for the study. Expression of AR and key players in IGF-1/PI3K/Akt signaling and angiogenesis was evaluated by qRT-PCR, immunoblotting, and immunohistochemistry. Molecular docking and simulation, overexpression, and knockdown experiments were performed to determine whether nimbolide targets AR and IGF-1R
Results:
Nimbolide inhibited AR with consequent blockade of the IGF-1/PI3K/Akt and HIF-1/VEGF signaling circuit by influencing the phosphorylation and intracellular localisation of key signaling molecules. Downregulation of DNMT-1, HDAC-6, miR-21, HOTAIR, and H19 with upregulation of miR-148a/miR-152 indicated that nimbolide regulates AR and IGF-1/PI3K/Akt signaling via epigenetic modifications. Coadministration of nimbolide with metformin and the chemotherapeutic drugs tamoxifen/cisplatin displayed higher efficacy than single agents in inhibiting IGF-1/PI3K/Akt/AR signaling. Grade-wise increases in IGF-1R and AR expression in breast cancer tissues underscore their value as biomarkers of progression.
Conclusions:
This study provides evidence for the anticancer effects of nimbolide in cellular and mouse models of breast cancer besides providing leads for new drug combinations. It has also opened up avenues for investigating potential molecules such as AR for therapeutic targeting of cancer.
Background and Objective:
The present study was undertaken to ascertain whether the modulatory
effects of blueberries on cell proliferation induced by Swedish snus in the rat forestomach epithelium is mediated
via abrogation of the PI3K/Akt/NFκB signaling axis that regulates cell fate decision.
Methods:
The transcript and protein expression of genes involved in cell cycle progression and apoptosis, as
well as canonical PI3K/Akt/NF-κB signaling pathways, were analyzed by qRT-PCR, immunoblotting and
ELISA. Expression profiling of noncoding RNAs (ncRNAs) that influence PI3K/Akt/NF-κB signaling was
undertaken. TUNEL assay was performed using flow cytometry.
Results:
Administration of snus induced basal cell hyperplasia in the rat forestomach with increased cell proliferation
and inhibition of apoptosis. This was associated with the activation of PI3K/Akt/NFκB signaling. Coadministration
of blueberries significantly suppressed snus-induced hyperplasia. Analysis of the molecular mechanisms
revealed that blueberries suppress the phosphorylation of Akt, NF-κB and IKKβ, prevent nuclear translocation
of NF-κB and modulate the expression of microRNAs that influence PI3K/Akt/NF-κB signaling.
Conclusion:
Taken together, the results of the current study provide compelling evidence that blueberries exert
significant protective effects against snus-induced soft tissue changes in the rat forestomach epithelium mediated
by inhibiting key molecular players in the PI3K/Akt/NF-κB signaling axis. Long-term studies on the impact
of snus exposure on various cellular processes, signaling pathways, and the interplay between genetic and epigenetic
mechanisms are however warranted. The results of this investigation may contribute to the development
of protection against soft tissue changes induced by smokeless tobacco in the human oral cavity.
The overall survival of patients with advanced serous adenocarcinoma of the ovary (EOC) has not significantly improved for the past 3 decades despite advances in treatment. In part, this is due to resistance of malignant cells and it is currently hypothesized that this could be due to persistence of cancer stem cells (CSC). Elimination of these cells may improve the survival of patients. RP6530 is a novel, potent, and selective PI3K δ/γ inhibitor that demonstrated high potency against PI3Kδ (IC50 = 25 nM) and γ (IC50 = 33 nM) enzymes with selectivity over α (>300-fold) and β (>100-fold) isoforms. A Phase-1 dose-escalation study to evaluate the safety and efficacy of RP6530 in patients with hematological malignancies in currently underway at several sites in Europe. The objective of this study was to test the efficacy of RP6530 against the CSC of EOC. A spheroid assay enriched for CSC was employed for this study. Initially, we have analyzed 3 cell lines (PEO4, OVCAR-5 and CAOV-2) with and without addition of 5 μM RP6530. In addition, MTT assay for cell viability was performed for the molecule to evaluate for non-selective cytotoxicity. To confirm that the target was CSC, we performed analysis of Side population (SP) based on H33342 dye exclusion. In the screening assay (triplicate and repeated thrice), RP6530 significantly inhibited spheroid formation in PEO4 and OVCAR-5 (p<0.05) and CAOV-2 (p<0.0005). In the cell viability assay, RP6530 had no cytotoxic effect in any of the cell lines. To evaluate the effect of the compound on CSC, we performed analysis of SP cells with Hoechst 33342 at 355 nm by flow cytometry. RP6530 either caused a reduction in the fraction of SP cells (PEO4 and CAOV-2) or was neutral (OVCAR-5) indicating that the compound preferentially targets CSC in ovarian cancer cell lines. Further in vitro and in vivo experiments are ongoing to conclusively prove this effect.
Citation Format: Sneha S, Nivetha R, Srikant Viswanadha, Swaroop Vakkalanka, Ganesan TS. RP6530, a dual PI3K δ/γ inhibitor attenuates cancer stem cell proliferation in serous adenocarcinoma of ovary. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3331.
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