Lens epithelium-derived growth factor (LEDGF) maintains survival pathways by augmenting the transcription of stress-response genes such as small heat-shock protein 27. Recently, aberrant expression of LEDGF was found in prostate cancer (PC). Herein, we showed that LEDGF overexpression upregulated Hsp27 in PC cells, DU145, PC-3 and LNCaP and promoted antiapoptotic pathways in PCs. We found that these cells had higher abundance of Hsp27, which was correlated with the levels of LEDGF expression. Transactivation assay in DU145 cells revealed that transactivation of Hsp27 was related to the magnitude of LEDGF expression. Silencing of LEDGF in DU145 cells abrogated Hsp27 expression and inhibited stimulated cell proliferation, invasiveness and migration. These cells were arrested in S and G2 phase, and failed to accumulate cyclin B1, and showed increased apoptosis. Furthermore, LEDGF-depleted DU145 cells displayed elevated Bax and cleaved caspase 9 expression and reduced levels of Bcl2, Bcl-XL. The activated survival pathway(s), ERK1/2 and Akt, were selectively decreased in these cells, which characteristically have lower tumorigenicity. Conversely, the depleted cells, when re-overexpressed with LEDGF or Hsp27, regained tumorigenic properties. Collectively, results reveal the involvement of LEDGF-mediated elevated expression of Hsp27-dependent survival pathway(s) in PC. Our findings suggest new lines of investigation aimed at developing therapies by targeting LEDGF or its aberrant expression-associated stimulated antiapoptotic pathway(s).
Background:
Several studies have revealed that abnormal activation of Notch signaling is closely
related with the development and progression of prostate cancer. Although there are numerous therapeutic
strategies, a more effective modality with least side effects is urgently required for the treatment of prostate
cancer. Carvacrol is a monoterpenoid phenol and majorly present in the essential oils of Lamiaceae family
plants. Many previous reports have shown various biological activities of carvacrol like antioxidant, antiinflammatory
and anticancer properties. Recently, we have shown potent anticancer property of carvacrol
against prostate cancer cell line DU145. In the current study, we report the chemopreventive and therapeutic
potential of carvacrol against another prostate cancer cell line PC-3 with its detailed mechanism of action.
Methods:
To determine the effect of the carvacrol on prostate cancer cells, the cell viability was estimated by
MTT assay and cell death was estimated by LDH release assay. The apoptotic assay was performed by DAPI
staining and FITC-Annexin V assay. Reactive Oxygen Species (ROS) was estimated by DCFDA method. Cell
cycle analysis was performed by flow cytometry. Gene expression analysis was performed by quantitative real
time PCR.
Results:
Our results suggested that the carvacrol treatment significantly reduced the cell viability of PC-3 cells
in a dose- and time-dependent manner. The antiproliferative action of carvacrol was correlated with apoptosis
which was confirmed by nuclear condensation, FITC-Annexin V assay, modulation in expression of Bax, Bcl-2
and caspase activation. The mechanistic insight into carvacrol-induced apoptosis leads to finding of elevated
level of Reactive Oxygen Species (ROS) and mitochondrial membrane potential disruption. Cell cycle analysis
revealed that carvacrol prevented cell cycle in G0/G1 that was associated with decline in expression of cyclin D1
and Cyclin-Dependent Kinase 4 (CDK4) and augmented expression of CDK inhibitor p21. Having been said the
role of hyperactivation of Notch signaling in prostate cancer, we also deciphered that carvacrol could inhibit
Notch signaling in PC-3 cells via downregulation of Notch-1, and Jagged-1.
Conclusion:
Thus, our previous and current findings have established the strong potential of carvacrol as a
chemopreventive agent against androgen-independent human prostate cancer cells.
Naturally occurring phytochemicals or plant derivatives are now being explored extensively for their health's benefits and medicinal uses. The therapeutic effect of phytochemicals has been reported in several pathophysiological settings such as inflammatory disorders, metabolic disorders, liver dysfunction, neurodegenerative disorders, and nephropathies. However, the most warranted therapeutic effects of phytochemicals were mapped to their anticancerous and chemopreventive action. Moreover, combining phytochemicals with standard chemotherapy has shown promising results in cancer therapy with minimal side effects and better efficacy. Many phytochemicals, like curcumin, resveratrol, and epigallocatechin‐3‐gallate, have been extensively investigated for their chemopreventive as well as chemotherapeutic effects. However, poor bioavailability, low solubility, hydrophobicity, and obscure target specificity restrict their therapeutic applications in the clinic. There has been a continually increasing interest to formulate nanoformulations of phytochemicals by using various nanocarriers, such as liposomes, micelles, nanoemulsions, and nanoparticles, to improve their bioavailability and target specificity, thereby maximizing the therapeutic potential. In the present review, we have summarized chemopreventive as well as chemotherapeutic action of some common phytochemicals and their major limitations in clinical application. Also, we have given an overview of strategies that can improve the efficacy of phytochemicals for their chemotherapeutic value in clinical settings.
Platinum containing drugs are widely used to treat advanced lung carcinomas. However, their clinical success is still limited due to severe side effects, and drug resistance. Alternative approaches are warranted to augment efficacy of platinum based chemotherapeutic drugs with minimal side effects. Intricatinol (INT), a homoisoflavonoid, has been shown to possess anti-tubercular, antioxidant, hypoglycaemic, and hypolipidemic activity. However, its anticancer activity largely remains unknown. In the present study, we have evaluated anticancer potential of INT alone or in combination with cisplatin (CIS) in non-small cell lung carcinoma (A549) cells. Treatment with INT alone reduced the viability of A549 cells in a dose-dependent manner. Interestingly, the combination of low doses of INT and CIS exerted a synergistic effect and induced apoptosis as evident by DNA fragmentation and Annexin V positive cells. Enhanced Bax:Bcl-2 ratio, loss of Δψm, cytochrome c release, cleavage of caspase 3 and PARP1 strongly corroborated our findings. Further, increased expression of p53, p38 MAPK and their phosphorylated counterparts, loss of clonogenicity and reduced migration potential were also recorded with INT + CIS treatment. Most interestingly, INT could not induce any significant cell death in primary mouse embryonic fibroblasts (MEFs). Moreover, no additive or synergistic effect was noted with INT + CIS in MEFs under similar treatment conditions. In conclusion, INT has a selective anticancer potential and could synergize cytotoxicity of CIS. Therefore, the combination of INT and CIS may serve as an effective anticancer strategy for the treatment of non-small cell lung carcinoma.
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