Regulation of Apoptosis during Environmental Skin Tumor Initiation

Skin cancer is more prevalent than any other cancer in the United States. Nonmelanoma skin cancers are the more common forms of skin cancer that affect individuals. The development of squamous cell carcinoma, the second most common type of skin cancer, can be stimulated by exposure of environmental carcinogens, such as chemical toxicants or UVB. It is developed by three distinct stages: initiation, promotion, and progression. During the initiation, the fate of DNA-damaged skin cells is determined by the homeostatic regulation of pro-apoptotic and antiapoptotic signaling pathways. The imbalance or disruption of either signaling will lead to the survival of initiated cells, resulting in the development of skin cancer. In this chapter, we will discuss signaling pathways that regulate apoptosis and the impact of their dysfunction during skin tumor initiation

Regulation of Apoptosis during Environmental Skin Tumor Initiation

Skin cancer is more prevalent than any other cancer in the United States. Nonmelanoma skin cancers are the more common forms of skin cancer that affect individuals. The development of squamous cell carcinoma, the second most common type of skin cancer, can be stimulated by exposure of environmental carcinogens, such as chemical toxicants or UVB. It is developed by three distinct stages: initiation, promotion, and progression. During the initiation, the fate of DNA-damaged skin cells is determined by the homeostatic regulation of pro-apoptotic and antiapoptotic signaling pathways. The imbalance or disruption of either signaling will lead to the survival of initiated cells, resulting in the development of skin cancer. In this chapter, we will discuss signaling pathways that regulate apoptosis and the impact of their dysfunction during skin tumor initiation

miRNA nanotherapeutics for cancer

miRNAs are noncoding RNA molecules that regulate gene expression through diverse mechanisms. Increasing evidence suggests that miRNA-based therapies, either restoring or repressing miRNA expression and activity, hold great promise. However, the efficient delivery of miRNAs to target tissues is a major challenge in the transition of miRNA therapy to the clinic. Cationic polymers or viral vectors are efficient delivery agents but their systemic toxicity and immunogenicity limit their clinical usage. Efficient targeting and sustained release of miRNAs/ anti-miRNAs using nanoparticles (NPs) conjugated with antibodies and/or peptides could reduce the required therapeutic dosage while minimizing systemic and cellular toxicity. Given their importance in clinical oncology, here we focus on the development of miRNA nanoformulations to achieve enhanced cellular uptake, bioavailability, and accumulation at the tumor site

Development of polyvinylpyrrolidone/paclitaxel self-assemblies for breast cancer

The goal of this investigation was to develop and demonstrate a polymer/paclitaxel self-assembly (PTX-SA) formulation. Polymer/PTX-SAs were screened based on smaller size of formulation using dynamic light scattering analysis. Additionally, fluorescence microscopy and flow cytometry studies exhibited that polyvinylpyrrolidone (PVP)-based PTX-SAs (PVP/PTX-SAs) had superior cellular internalization capability in MCF7 and MDA-MB-231 breast cancer cells. The optimized PVP/PTX-SAs exhibited less toxicity to human red blood cells indicating a suitable formulation for reducing systemic toxicity. The formation of PVP and PTX self-assemblies was confirmed using fluorescence quenching and transmission electron microscopy which indicated that the PVP/PTX-SAs were spherical in shape with an average size range of 53.81 nm as detected by transmission electron microscopy (TEM). FTIR spectral analysis demonstrates incorporation of polymer and paclitaxel functional groups in PVP/PTX-SAs. Both proliferation (MTS) and clonogenic (colony formation) assays were used to validate superior anticancer activity of PVP/PTX-SAs in breast cancer cells over paclitaxel. Such superior anticancer activity was also demonstrated by downregulation of the expression of pro-survival protein (Bcl-xL), upregulation of apoptosis-associated proteins (Bid, Bax, cleaved caspase 7, and cleaved PARP) and β-tubulin stabilization. These results support the hypothesis that PVP/PTX-SAs improved paclitaxel delivery to cancer cells

Novel Paclitaxel Nanoformulation Impairs De Novo Lipid Synthesis in Pancreatic Cancer Cells and Enhances Gemcitabine Efficacy

Pancreatic cancer (PanCa) is a highly lethal disease with a poor 5 year survival rate, less than 7%. It has a dismal prognosis, and more than 50% of cases are detected at an advanced and metastatic stage. Gemcitabine (GEM) is a gold standard chemotherapy used for PanCa treatment. However, GEM-acquired resistance in cancer cells is considered as a major setback for its continued clinical implementation. This phenomenon is evidently linked to de novo lipid synthesis. PanCa cells rely on de novo lipid synthesis, which is a prime event in survival and one of the key drivers for tumorigenesis, cancer progression, and drug resistance. Thus, the depletion of lipogenesis or lipid metabolism can not only improve treatment outcomes but also overcome chemoresistance, which is an unmet clinical need. Toward this effort, our study reports a unique paclitaxel−poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PPNPs) formulation which can target lipid metabolism and improve anticancer efficacy of GEM in PanCa cells. PPNPs inhibit excessive lipid formation and alter membrane stability with compromised membrane integrity, which was confirmed by Fourier transform infrared and zeta potential measurements. The effective interference of PPNPs in lipid metabolic signaling was determined by reduction in the expression of FASN, ACC, lipin, and Cox-2 proteins. This molecular action profoundly enhances efficacy of GEM as evident through enhanced inhibitory effects on the tumorigenic and metastasis assays in PanCa cells. These data clearly suggest that the ablation of lipid metabolism might offer an innovative approach for the improved therapeutic outcome in PanCa patients

Magnetic Nanoformulations for Prostate Cancer

Magnetic nanoparticles (MNPs) play a vital role for improved imaging applications. Recently, a number of studies demonstrate MNPs can be applied for targeted delivery, sustained release of therapeutics, and hyperthermia. Based on stable particle size and shape, biocompatibility, and inherent contrast enhancement characteristics, MNPs have been encouraged for pre-clinical studies and human use. As a theranostic platform development, MNPs need to balance both delivery and imaging aspects. Thus, this review provides significant insight and advances in the theranostic role of MNPs through the documentation of unique magnetic nanoparticles used in prostate cancer, their interaction with prostate cancer cells, in vivo fate, targeting, and biodistribution. Specific and custom-made applications of various novel nanoformulations in prostate cancer are discussed

Ultraviolet radiation-induced tumor necrosis factor alpha, which is linked to the development of cutaneous SCC, modulates differential epidermal microRNAs expression

Chronic exposure to ultraviolet radiation (UVR) is linked to the development of cutaneous squamous cell carcinoma (SCC), a non-melanoma form of skin cancer that can metastasize. Tumor necrosis factor-alpha (TNFα), a pro-inflammatory cytokine, is linked to UVR-induced development of SCC. To find clues about the mechanisms by which TNFα may promote UVR-induced development of SCC, we investigated changes in the expression profiling of microRNAs (miRNA), a novel class of short noncoding RNAs, which affects translation and stability of mRNAs. In this experiment, TNFα knockout (TNFα KO) mice and their wild type (WT) littermates were exposed to acute UVR (2.0 kJ/m2) and the expression profiling of epidermal miRNA was determined 4hr post UVR exposure. TNFα deletion in untreated WT mice resulted in differential expression (log fold change\u3e1) of seventeen miRNA. UVR exposure in WT mice induced differential expression of 22 miRNA. However, UVR exposure in TNFα KO mice altered only two miRNAs. Four miRNA, were differentially expressed between WT+UVR and TNFα KO+UVR groups. Differentially expressed selected miRNAs were further validated using real time PCR. Few of the differentially expressed miRNAs (miR-31-5p, miR-196a-5p, miR-127-3p, miR-206-3p, miR-411-5p, miR-709, and miR-322-5p) were also observed in UVR-induced SCC. Finally, bio-informatics analysis using DIANA, MIRANDA, Target Scan, and miRDB algorithms revealed a link with major UVR-induced pathways (MAPK, PI3K-Akt, transcriptional mis-regulation, Wnt, and TGF-beta)

Pharmacological restoration of PKD1: A novel strategy for prostate cancer therapy

Background: Prostate cancer has poor prognosis owing to late diagnosis and ineffective multimodal clinical treatment. Extensive efforts are ongoing to establish methods that can resolve the expression of genes implicated in disease development and treatment. Previously, we reported that Protein Kinase D1 (PKD1), a serine threonine kinase, controls a number of tumor suppressor functions including cell aggregation, cell motility, cell proliferation, and cell invasion. Thus, PKD1 is considered as an emerging therapeutic target for prostate cancer treatment. Objective: To investigate the restoration of PKD1 by a pharmacological modulator ormeloxifene, which showed well-defined PK/PD and safety profiles in humans. Methods: Proliferation, clonogenicity, migration, invasion, western blotting and qPCR analysis were performed to investigate the anticancer effect of ORM, docetaxel and/or their combination on PKD1 and related signaling mechanisms in prostate cancer. Results: ORM treatment inhibited cell proliferation, invasion, migration and colony formation abilities of prostate cancer cells in a dose-dependent manner compared to vehicle treated group. ORM treatment selectively induces the expression of PKD1 both at mRNA and protein levels in C4-2 cells. Moreover, our results have also shown that ORM effectively attenuates MTA1 expression in prostate cancer cells. MTA1 physically interact and shown to have inverse relationship with PKD1. In addition, we observed that ORM treatment enhances the therapeutic efficacy of docetaxel in C4-2 cells. Our results also indicate that ORM treatment potentiate the effects of docetaxel as determined by MTS and colony formation assays. Conclusion: These results suggest that ORM exhibit potent anticancer activity via restoration of PKD1 in prostate cancer

Molecular Insights into Targeting PKD1 for Prostate Cancer Treatment

Background: Prostate cancer has a poor prognosis due to late diagnosis and ineffective multimodal clinical treatment. Efforts are underway to create strategies for resolving the abnormal expression of molecular targets implicated in disease development and progression. We previously reported that the serine threonine kinase Protein Kinase D1 (PKD1) regulates a multitude of tumor suppressor functions, including cell aggregation, motility, proliferation, and invasion in prostate cancer. Thus, PKD1 is regarded as a promising therapeutic target for the treatment of prostate cancer. Objective: The goal of this study was to investigate the therapeutic potential of ormeloxifene (ORM), a pharmacological modulator with well-defined PK/PD and safety profiles in humans, for PKD1 restoration in prostate cancer. Methods: The anticancer effect of ORM on PKD1 and associated signaling mechanisms in prostate cancer was investigated using proliferation, clonogenicity, migration, invasion, western blotting, and qPCR analysis. Results: In comparison to the vehicle-treated group, ORM treatment decreased prostate cancer cell proliferation, invasion, migration, and colony formation in a dose-dependent manner. In C4-2 cells, ORM treatment selectively induces PKD1 expression at both the mRNA and protein levels. Furthermore, our findings revealed that ORM efficiently suppresses MTA1 expression in prostate cancer cells. MTA1 physically interacts with PKD1 and has been shown to have an inverse correlation with it. Our results also showed that ORM treatment enhances the therapeutic efficacy of decetaxel. Conclusion: Taken together, these findings show that ORM has anticancer properties in prostate cancer via restoring PKD1

A triphenylethylene nonsteroidal SERM attenuates cervical cancer growth

Selective estrogen receptor modulator drug molecules of triphenylethylene family have gained considerable attention as anti-cancer agents. Despite recent advances in screening and development of HPV vaccines, cervical cancer remains one of the deadliest malignancies as advanced stage metastatic disease is mostly untreatable, thus warrants newer therapeutic strategies. Ormeloxifene (ORM) is a well-known SERM of triphenylethylene family that has been approved for human use, thus represents an ideal molecule for repurposing. In this study, we for the first time have demonstrated the anti-cancerous properties of ormeloxifene in cervical cancer. Ormeloxifene efficiently attenuated tumorigenic and metastatic properties of cervical cancer cells via arresting cell cycle at G1-S transition, inducing apoptosis, decreasing PI3K and Akt phosphorylation, mitochondrial membrane potential, and modulating G1-S transition related proteins (p21, cyclin E and Cdk2). Moreover, ORM repressed the expression of HPV E6/ E7 oncoproteins and restored the expression of their downstream target tumor suppressor proteins (p53, Rb and PTPN 13). As a result, ormeloxifene induces radio-sensitization in cervical cancer cells and caused potent tumor growth inhibition in orthotopic mouse model. Taken together, ormeloxifene represents an alternative therapeutic modality for cervical cancer which may have rapid clinical translation as it is already proven safe for human use