BackgroundDespite recent advances in diagnosis and treatment, prostate cancer (PCa) remains the leading cause of cancer-related deaths in men. Current treatments offered in the clinics are often toxic and have severe side effects. Hence, to treat and manage PCa, new agents with fewer side effects or having potential to reduce side effects of conventional therapy are needed. In this study, we show anti-cancer effects of quercetin, an abundant bioflavonoid commonly used to treat prostatitis, and defined quercetin-induced cellular and molecular changes leading to PCa cell death.MethodsCell viability was assessed using MTT. Cell death mode, mitochondrial outer membrane potential, and oxidative stress levels were determined by flow cytometry using Annexin V-7 AAD dual staining kit, JC-1 dye, and ROS detection kit, respectively. Antibody microarray and western blot were used to delineate the molecular changes induced by quercetin.ResultsPCa cells treated with various concentrations of quercetin showed time- and dose-dependent decrease in cell viability compared to controls, without affecting normal prostate epithelial cells. Quercetin led to apoptotic and necrotic cell death in PCa cells by affecting the mitochondrial integrity and disturbing the ROS homeostasis depending upon the genetic makeup and oxidative status of the cells. LNCaP and PC-3 cells that have an oxidative cellular environment showed ROS quenching after quercetin treatment while DU-145 showed rise in ROS levels despite having a highly reductive environment. Opposing effects of quercetin were also observed on the pro-survival pathways of PCa cells. PCa cells with mutated p53 (DU-145) and increased ROS showed significant reduction in the activation of pro-survival Akt pathway while Raf/MEK were activated in response to quercetin. PC-3 cells lacking p53 and PTEN with reduced ROS levels showed significant activation of Akt and NF-κB pathway. Although some of these changes are commonly associated with oncogenic response, the cumulative effect of these alterations is PCa cell death.ConclusionsOur results demonstrated quercetin exerts its anti-cancer effects by modulating ROS, Akt, and NF-κB pathways. Quercetin could be used as a chemopreventive option as well as in combination with chemotherapeutic drugs to improve clinical outcomes of PCa patients.
Colon cancer patients receiving chemotherapy continue to be burdened with therapeutic failure and adverse side effects, yielding a need to develop more effective treatments. The present study investigates Cinnamtannin B-1 (CTB-1) as a potential low-toxicity therapeutic alternative for colon cancer. CTB-1-treated DLD-1, COLO 201 and HCT-116 (WT p53 and p53 null) colon cancer cells and CCD 841 CoN normal colon epithelial cells were assessed for changes in survival using MTT assay. The effects of CTB-1 on cell cycle progression and the apoptosis of colon cancer cells were measured using flow cytometry and/or immunofluorescence. The expression profiles of cell survival molecules, particularly apoptotic proteins, in the colon cancer cells were evaluated following CTB-1 treatment via antibody array, then validated by western blot analysis. Additionally, the potential synergy between CTB-1 and 5-fluorouracil (5-FU), a conventional chemotherapeutic agent used in the treatment of colon cancer, against colon cancer cells was assessed using MTT assay and Calcusyn software. The results revealed that CTB-1 signifi-cantly decreased the survival of the DLD-1, COLO 201 and HCT-116 cells in a time and/or dose-dependent manner, with minimal cytotoxicity to normal colon cells. CTB-1 treatment was shown to induce cell cycle arrest and apoptosis of DLD-1 and COLO 201 cells. Of note, CTB-1 modulated the expression of several cell survival molecules, which tend to be deregulated in colon cancer, including p53, a key transcription factor involved in apoptosis. The downstream regulation of Bcl-2 and Bak expression, as well as cytochrome c release into the cytosol, was also observed following CTB-1 treatment. Furthermore, CTB-1 was shown to significantly enhance the potency of 5-FU via a synergistic drug interaction. This study reveals for the first time, to the best of our knowledge, the ability of CTB-1 to decrease the survival of colon cancer cells through pro-apoptotic mechanisms and display synergy with conventional chemotherapy, demonstrating the potential therapeutic benefit of CTB-1 in colon cancer.
Lung cancer is the leading cause of cancer related deaths worldwide in both men and women. Metastasis is responsible for most lung cancer related deaths; therefore, a better understanding of the metastatic processes and therapies designed to prevent the spread of cancer cells are greatly needed. The specific mechanisms that promote metastases have not been fully elucidated. Among all known chemokine receptors involved in cancer progression, most cancer cells including lung cancer express CXCR4. Furthermore, involvement of CXCR4 and CCR7 in breast cancer and CXCR4, CCR9 and CX3CR1 in prostate cancer progression further indicates that multiple chemokine receptors are involved in dictating the multi-step process of metastasis. In this study, we show significantly higher expression of CXCR6 and CXCL16 in lung cancer tissues compared to normal matched tissues. Expression of CXCR6 was significantly higher in adeno- carcinoma compared to squamous cell carcinoma. It addition to these, serum levels of CXCL16, the only natural ligand for CXCR6, was also significantly higher in lung cancer patients compared to normal healthy donor. Furthermore, serum CXCL16 was also significantly higher in patients with adenocarcinoma compared to patients with squamous cell carcinoma. Impact of this chemokines-receptor axis was determined in lung cancer cell lines in vitro, which express CXCR6 and CXCL16. Like tissues, lung cancer cells showed higher expression of CXCR6 and CXCL16 compared to normal lung epithelial cells (NuLi-1). Interestingly, expression of CXCR6 was highest in cell lines derived form adenocarcinoma followed by cell lines from squamous cell carcinoma. Furthermore, we demonstrate that CXCR6 and soluble CXCL16 interaction plays a crucial role in lung cancer cells migration and invasion. The mechanism underlying these clinically and biologically important findings need to be further explored. Increased serum CXCL16 in lung cancer patients with metastatic disease required further validation as a potential therapeutic target and/or diagnostic marker for lung cancer. Citation Format: Hina Mir, Pranav Gupta, Rajesh Singh, Praveen K. Sharma, Gurpreet Kaur, Ashley B. Ward, William E. Grizzle, James W. Lillard, Shailesh Singh. Clinical and biological significance of CXCR6 in lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4003. doi:10.1158/1538-7445.AM2014-4003
Prostate cancer (PCa) affects nearly 80% of men worldwide and is the second leading killer after lung cancer. The efficacy of current treatments offered in the clinics is highly compromised due to indolent nature of PCa, which provides large window of opportunity for prevention. Hence, the major focus of this study is to determine the chemo-preventive effects of Quercetin, a bioflavonoid, on prostate cancer. Effect of Quercetin on cell viability and IC50 was determined by MTT assay. The effect of Quercetin on cell motility was determined by wound healing assay. Potential role of Quercetin on cell cycle, apoptosis as well as genes involved in cell motility and invasion was determined using flow cytometry, Real-time qPCR and ELISA. Furthermore, Quercetin induced changes in signaling molecules involved in cell survival/apoptosis, cell cycle and cytoskeletal rearrangement was determined using antibody microarray. Prostate cancer cells treated with Quercetin showed dose and time dependent inhibition of proliferation/viability, and induction of apoptosis as compared to normal prostatic epithelial cells and untreated controls. Prostate cancer cell motility was inhibited in Quercetin treated cells. Prostate cancer cells were arrested in G2 phase of the cell cycle following Quercetin treatment. In addition to these, we found differential expression of caspases, matrix metalloproteinases (MMPs) and tissue inhibitor of MMPs in different PCa cell lines compared to untreated controls. Furthermore, antibody microarray analysis demonstrated selective modulation of genes and associated signaling cascades responsible for apoptosis induction, cellular motility, adhesion and invasion in Quercetin treated cells compared to controls. These findings suggest Quercetin as a potent chemo-preventive agent. In addition to this it can be also used with chemotherapeutic agents directed to G2 phase of the cell cycle, which may improve the efficacy of chemotherapeutics offered in clinics to treat advance prostate cancer. Citation Format: Ashley B. Ward, Pranav Gupta, Gurpreet Kaur, Hina Mir, James W. Lillard, Shailesh Singh. The effects of Quercetin on prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2128. doi:10.1158/1538-7445.AM2014-2128
Despite recent advances in treatment and clinical management, prostate cancer is still a leading cause of cancer related deaths among men, primarily because etiopathogenesis of PCa is not well defined. In this regard, chemokines and their corresponding receptors have been shown to play major role in PCa progression, which are often associated with poor therapeutic outcomes. Hence, the focus of this study is to determine the potential role of CXCR6 and its natural ligand CXCL16 in PCa pathogenesis, and potential impact of CXCR6-CXCL16 axis on efficacy of docetaxel, which is currently offered in the clinics as standard care. We investigated expression of CXCR6 and CXCL16 in clinical samples, prostate cancer cell lines and normal prostatic epithelial cells. Expression of CXCR6 and CXCL16 was significantly higher in PCa samples compared to their respective controls, and expression of CXCR6/ CXCL16 was correlated with tumor stage and grades. Similar to patient's samples, expression of CXCR6/CXCL16 was significantly higher in PCa cell lines compared to normal prostatic epithelial cells. Furthermore, levels of phospho -ERK1/2 and -NF-kB, known to be involved in cell growth and survival, were significantly higher in PCa cells treated with CXCL16 compared to untreated controls. In addition to these, role of CXCR6- CXCL16 on genes responsible for cellular adhesion and epithelial-mesenchymal transition were examined. Interestingly, expression of surface E-cadherin and β−catenin following CXCL16 treatment was significantly inhibited compared to untreated cells, suggesting the involvement of CXCR6-CXCL16 interaction in PCa cell migration. Additionally, CXCR6 expressing PCa cells expressed higher α−smooth muscle actin protein, another EMT marker presumably induced by elevated TGF-β, following CXCL16 stimulation. Furthermore, expression of CXCR6, CXCL16 and MMP(s) were elevated in PCa cell following docetaxel treatment in a time and dose dependent manner compared to controls. This may explain the increased efficacy of docetaxel when used in combination with anti-CXCR6 antibody as compared to docetaxel alone. These findings suggest that CXCR6-CXCL16 axis plays a crucial role in pathogenesis of PCa, and inhibition of this axis may have significant impact on disease progression and therapeutics outcomes. Citation Format: Pranav Gupta, Ashley B. Ward, Hina Mir, Gurpreet Kaur, William E. Grizzle, James W. Lillard, Shailesh Singh. Potential role of CXCR6-CXCL16 in prostate cancer progression and chemotherapeutic efficacy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4047. doi:10.1158/1538-7445.AM2014-4047
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