Apoptotic Switch in Cancer Stem Cells: A Potential Approach for Cancer Treatment.

Cancer diseases account for about 15% of deaths globally right now, and the percentage may increase in the future. There are more than 100 types of cancer, and each of them is distinct in its origin, microenvironment, growth, metastasis, and signalling pathways. Cancer stem cells are the specialised cells that make cancer more aggressive and difficult to treat. Moreover, cancer aetiology may exist at the genomic, proteomic, or habitat level in any combination. Hence, a unanimous treatment protocol for the different cancers is an uphill task at the present juncture. In this context, this review aims to provide a comprehensive reappraisal concisely of anti-apoptotic proteins, which are shown to be overexpressed in most cancers, if not all, and to forthrightly rationalise the apoptotic proteins as potential biomarkers and druggable targets of the cancers by effectively killing cancer stem cells.

A critical review on starch-based electrospun nanofibrous scaffolds for wound healing application.

Starch-based nanofibrous scaffolds exhibit a potential wound healing processes as they are cost-effective, flexible, and biocompatible. Recently, natural polymers have received greater importance in regenerative medicine, mainly in the process of healing wounds and burns due to their unique properties which also include safety, biocompatibility, and biodegradability. In this respect, starch is considered to be one of the reliable natural polymers to promote the process of wound healing at a significantly faster rate. Starch and starch-based electrospun nanofibrous scaffolds have been used for the wound healing process which includes the process of adhesion, proliferation, differentiation, and regeneration of cells. It also possesses significant activity to encapsulate and deliver biomaterials at a specific site which persuades the wound healing process at an increased rate. As the aforementioned scaffolds mimic the native extracellular matrix more closely, may help in the acceleration of wound closure, which in turn may lead to the promotion of tissue reorganization and remodeling. In-depth knowledge in understanding the properties of nanofibrous scaffolds paves a way to unfold novel methods and therapies, also to overcome challenges associated with wound healing. This review is intended to provide comprehensive information and recent advances in starch-based electrospun nanofibrous scaffolds for wound healing.

Tumor-derived osteopontin drives the resident fibroblast to myofibroblast differentiation through Twist1 to promote breast cancer progression.

Tumor-stroma interactions are important determinants for the disease course in cancer. While stromal influence has been known to often play a tumor-promoting role, incomplete mechanistic insight into this phenomenon has prevented its therapeutic targeting. Stromal fibroblasts can be activated by tumor cells to differentiate into cancer-associated fibroblasts (CAFs), that exhibit the traits of myofibroblasts, and in turn, they increase cancer aggressiveness. Here, we report the crosstalk between the cancer cells and stromal fibroblasts that leads to tumor progression. The process is initiated by secretion of a chemokine like protein, osteopontin (OPN) from the cancer cells that differentiates the fibroblasts to myofibroblasts. Tumor-derived OPN achieves this transition by engaging CD44 and αvß3 integrins on the fibroblast surface, which mediates signaling via Akt and ERK to induce Twist1-dependent gene expression. The OPN-driven CAFs then secrete CXCL12, which in turn triggers epithelial to mesenchymal transition (EMT) in the tumor cells. OPN, produced by the cancer cells, and CXCL12, secreted by activated fibroblasts, are necessary and sufficient to perpetuate the crosstalk. Knocking out OPN in carcinogen-induced mammary tumors or knocking down OPN in cancer cells and fibroblast co-implanted xenografts abrogates myofibroblast differentiation, Twist1, and CXCL12 expression. OPN expression is correlated with CAF-specific gene signature as shown by breast tumor tissue microarray consisting of 100 patient specimens. Bioinformatics analyses have confirmed that the expression of OPN is significantly correlated with the expression of myofibroblast-specific markers as demonstrated in human breast carcinoma dataset of 2509 patients. Our findings describe OPN and CXCL12 act as compelling targets to curb the tumor-promoting features of the stromal components and further suggested that OPN-regulated CXCL12 network might act as potential therapeutic target for the management of CAF-mediated breast cancer progression.

p-Coumaric acid attenuates alcohol exposed hepatic injury through MAPKs, apoptosis and Nrf2 signaling in experimental models.

Overconsumption of alcohol could lead to severe liver injury that connects with oxidative stress, apoptosis, and inflammatory response. Previously, we proved that p-coumaric acid prevents ethanol induced reproductive toxicity; however, p-coumaric acid (PCA) on ethanol mediated hepatotoxicity has not been examined yet. In our work, we sought to study the potential of PCA in contradiction of ethanol induced hepatoxicity which linking with MAPKs, apoptosis, oxidative stress, and Nrf2 signaling. Foremost, we found that PCA could protect ethanol induced both L-02 and HepG2 hepatic cells by inhibiting cytotoxicity, ROS production, mitochondrial depolarization, and nuclear fragmentation. Also, in vivo experiments showed that the ethanol increasing the lipid markers (TBARS, CD) and depletes the antioxidants thereby increased phosphorylation of JNK, ERK, and p38 in rat liver tissues. Interestingly, PCA treatments inhibit ethanol exposed lipid markers and depletion of antioxidants, which directs the inhibition of MAPKs activation in rat liver tissues. We also noticed that the PCA protected ethanol induced apoptosis and liver markers by inhibiting the expression of Bax, caspases; AST, ALT, ALS, and LDH in liver tissue. Overall, the ameliorative consequence of PCA on ethanol induced oxidative stress and apoptosis was achieved by suppressing the expression of CYP2E1 and overexpressing Nrf2 and its target protein HO-1 in rat liver tissue. As a result, PCA was marked to be an effective antioxidant with notable hepatoprotection by inhibiting MAPKs and apoptosis signaling via enhancing Nrf2 signaling.

Breast cancer stem cells: Biology and therapeutic implications.

Breast cancer remains to be a dreadful disease even with several advancements in radiation and chemotherapies, owing to the drug resistance and tumor relapse caused by breast cancer stem cells. Cancer stem cells are a minute population of cells of solid tumors which show self-renewal and differentiation properties as well as tumorigenic potential. Several signaling pathways including Notch, Hippo, Wnt and Hedgehog and tumor-stroma exchanges play a critical role in the self-renewal and differentiation of cancer stem cells in breast cancer. Cancer stem cells can grow anchorage-independent manner so they disseminate to different parts of the body to form secondary tumors. Cancer stem cells promote angiogenesis by dedifferentiating to endothelial cells as well as secreting proangiogenic and angiogenic factors. Moreover, multidrug resistance genes and drug efflux transporters expressed in breast cancer stem cells confer resistance to various conventional chemotherapeutic drugs. Indeed, these therapies are recognised to enhance the percent of cancer stem cell population in tumors leading to cancer relapse with increased aggressiveness. Hence, devising the therapeutic interventions to target cancer stem cells would be useful in increasing patients' survival rates. In addition, targeting the self-renewal pathways and tumor-stromal cross-talk helps in eradicating this population. Reversal of the cancer stem cell-mediated drug resistance would increase the sensitivity to various conventional drugs for the effective management of breast cancer. In this review, we have discussed the cancer stem cell origin and their involvement in angiogenesis, metastasis and therapy-resistance. We have also summarized different therapeutic approaches to eradicate the same for the successful treatment of breast cancer.

Protective effects of p­coumaric acid on ethanol induced male reproductive toxicity.

Alcohol, a psychoactive drug is one of the lifestyle factors responsible for male infertility. Present study was carried out to investigate the ameliorative effect of p­coumaric acid (PCA), a plant derived bioactive phenolic compound on alcohol induced chronic reproductive toxicity in male rats. Thirty male Wistar rats were divided into five groups, each with six animals. Group I as control received vehicle (distilled water) alone. And the following Group II, III, IV, V were treated orally with sequentially (per week) increased dose of ethanol 25% v/v (5, 8, 10 and 12 g/kg b wt per week in each group) for 28 days. On the 3rd and 4th week, the groups III, IV, V were administered with p­coumaric acid orally at three different concentrations (Low 50 mg/kg b wt; Medium 100 mg/kg b wt; High 200 mg/kg b wt). The rats treated with ethanol showed abnormal sperm characteristics, reduced anti-oxidant level, reduced testosterone level and abnormal testicular histoarchitecture while the rats treated with PCA in addition to ethanol were found to have protective effects on sperm parameters and apoptosis. The increased caspase-3, caspase-7, p21 immunoreactivity and reduced Cdk4 immunoreactivity in ethanol treated rats confirmed that ethanol increases the apoptosis in testis and a reduced expression in the rats treated with PCA in addition to ethanol indicates a protective role of PCA. Overall, our results showed that PCA mitigates alcohol induced male reproductive toxicity and improves reproductive health in male Wistar rats.

Receptor tyrosine kinases (RTKs) in breast cancer: signaling, therapeutic implications and challenges.

Breast cancer is a multifactorial disease and driven by aberrant regulation of cell signaling pathways due to the acquisition of genetic and epigenetic changes. An array of growth factors and their receptors is involved in cancer development and metastasis. Receptor Tyrosine Kinases (RTKs) constitute a class of receptors that play important role in cancer progression. RTKs are cell surface receptors with specialized structural and biological features which respond to environmental cues by initiating appropriate signaling cascades in tumor cells. RTKs are known to regulate various downstream signaling pathways such as MAPK, PI3K/Akt and JAK/STAT. These pathways have a pivotal role in the regulation of cancer stemness, angiogenesis and metastasis. These pathways are also imperative for a reciprocal interaction of tumor and stromal cells. Multi-faceted role of RTKs renders them amenable to therapy in breast cancer. However, structural mutations, gene amplification and alternate pathway activation pose challenges to anti-RTK therapy.

Doxorubicin-induced female reproductive toxicity: an assessment of ovarian follicular apoptosis, cyclicity and reproductive tissue histology in Wistar rats.

Doxorubicin is a widely used chemotherapeutic agent for various cancers, particularly for the female breast cancer patients. Although the rate of young female cancer patients is increasing every year, conversely the lack of knowledge of adverse effects of doxorubicin on female reproductive system insisted us to assess the toxic effects of doxorubicin on the female reproductive tissue histoarchitecture, cyclicity, and mammary glands in Wistar rats. The rats were divided into two groups depending on the treatment period, i.e., 24 h and 28 d and further subdivided into three subgroups and administered with doxorubicin at 3 mg/kg bw (subgroup I), 6 mg/kg bw (subgroup II), and equal volume of normal saline (subgroup III) intraperitoneally once during the whole treatment period. We observed a significantly altered estrous cycle with a prolonged diestrous and short proestrous in higher dose group and dose-dependent significant changes in the uteri and mammary gland histoarchitecture in 28 days treated rats as compared to control. Moreover, the micronuclei and chromosomal aberration frequency were increased significantly in both treatment groups. A significant increase in follicular atresia in ovaries of the 28 days treated rats was observed. The immunohistochemical analysis of ovarian tissues showed an increased p53 and caspase 3 expression and apoptosis in primordial follicles of treated rats. The results suggest that though doxorubicin is a potential chemotherapeutic drug for many tumors, but the risk of adverse effects on the female reproductive system is there even at low doses.

Identification of 2,4-dihydroxy-5-pyrimidinyl imidothiocarbomate as a novel inhibitor to Y box binding protein-1 (YB-1) and its therapeutic actions against breast cancer.

In spite of advances in breast cancer treatment and early diagnosis, drug toxicity, cancer relapse, multidrug resistance and metastasis are the major impediment to the developments of efficient drugs. However, unique druggable targets of cancer cells distinct from the normal cells provide new rationale in cancer treatment. Previous reports clearly emphasize the differential expression and localization of Y box binding protein-1 (YB-1) between normal breast tissues and different stages of breast cancer. Y box binding protein-1 is DNA as well as RNA binding protein involved in transcription and translation regulation of various proteins involved in cancer progression, apoptosis, cell cycle, epithelial to mesenchymal transition (EMT) and drug resistance. Particularly, during doxorubicin (DOX) treatment and cancer relapse conditions, YB-1 expression was very high in breast cancer tissues and localized in to nucleus which further favours DOX efflux and metastasis. Moreover, siRNA mediated silencing of YB-1 reduces breast cancer progression and metastasis. In this rationale, using an array of computational methods, 2,4-dihydroxy-5-pyrimidinyl imidothiocarbomate (DPI) has been screened out as a drug-likeness antagonist to the YB-1for cancer treatment. In this study, we determined that DPI was toxic to breast cancer cell lines as individual drug as well as in combination with DOX. Moreover, immunofluorescence and confocal studies showed that DPI decreases DOX induced YB-1 nuclear translocation and increases DOX accumulation in breast cancer cell line. A G1/G0 phase cell cycle arrest and apoptosis was also induced by DPI. Moreover, DPI modulated YB-1 downstream targets such as p53, caspase-3, CDK-1 which are involved in cell cycle progression and apoptosis. Further, metastatic functional analysis revealed that DPI inhibits cell adhesion, migration, invasion in aggressive metastatic cell line and inhibits angiogenesis in chick embryonic chorioallantoic membrane (CAM) model. Meanwhile, DPI alters the expression of YB-1 downstream targets which are involved in metastasis such as VEGFR, caveolin, E-cadherin, cytokeratins, desmin and vimentin in MDA-MB-231 xenograft in chick embryonic CAM membrane. The results clearly demonstrated that DPI inhibited YB-1 nuclear translocation, thereby exhibited anti-apoptotic, anti-proliferative and anti-metastatic activities and increases the therapeutic potential of commercial breast cancer drug doxorubicin.

Inverse correlation of ribosomal protein S27A and multifunctional protein YB-1 in hepatocellular carcinoma.

OBJECTIVE: The detection of possible correlation between ribosomal protein RPS27A and multifunctional YB-1 expression in hepatocellular carcinoma (HCC). DESIGN AND METHODS: Tissue microarray slides containing totally 80 cores with 19 tissues of HCC, 1 tissue of hepatocholangiocarcinoma, 10 tissues of liver cirrhosis and 10 normal liver tissues in duplicates were analyzed for expression of RPS27A and YB-1 by immunohistochemistry. RESULTS: Among each of 10 LC and normal liver tissues all (100%) showed RPS27A positive expression but only 11 out of 19 HCC tissues (57.89%) showed RPS27A positive expression with significant difference compared (P<0.05) with both LC and normal tissues. We found positive expression of YB-1 in 17 tissues out of 19 HCC tissues (89.47%) but only 4 tissues out of each 10 LC as well as normal liver tissues showed positive expression with significant (P<0.01) difference compared to HCC tissues. A statistically significant inverse weak correlation (rho=-0.293) between YB-1 expression and RPS27A expression was found. CONCLUSION: The present investigation concludes that the ribosomal protein RPS27A was down-regulated in viral induced HCC patients. RPS27A expression was found to have a weak inverse correlation with overexpression of multifunctional protein YB-1 in HCC tissues. This study opens up a new window for YB-1-RPS27A axis in HCC.