Withaferin A-Encapsulated PEGylated Nanoliposomes Induce Apoptosis in B16F10 Melanoma Cells by Regulating Bcl2 and Bcl xl Genes and Mitigates Murine Solid Tumor Development.

Withaferin A (WA) is a natural steroidal lactone with promising pharmacological activities, but its poor solubility and bioavailability hinder its clinical application. The liposomal drug delivery system has attracted considerable attention to overcome the delivery limitations of pharmacological agents. The present study investigated the effect of WA-loaded pegylated nanoliposomes (LWA) on in vitro and in vivo B16F10 melanoma tumor models. In vitro results showed that LWA had significantly (P < 0.01) higher cytotoxicity than free WA and induced ROS-mediated apoptosis in B16F10 cells. Transwell cell migration and invasion studies demonstrated that LWA treatment significantly (P < 0.01) decreased the migratory and invasive capacities of melanoma cells compared with WA. In vivo study revealed that treatment significantly (P < 0.01) reduced tumor growth in experimental animals compared with WA or tumor control. Also, LWA administration remarkably inhibited tumor cell proliferation by downregulating the expression of Ki-67 and Cyclin D1 and induced apoptosis by regulating the expression of Bax, Bcl2, and Bcl xl levels. Our results strongly suggest that LWA could be a promising therapeutic formulation for treating malignant melanoma.

AS1411 aptamer tagged PEGylated liposomes as a smart nanocarrier for tumor-specific delivery of Withaferin A for mitigating pulmonary metastasis.

Metastasis is the most challenging health problem contributing to about 90 % of cancer-related deaths worldwide. Metastatic tumors are highly aggressive and resistant to the most available therapeutic options. Hence, innovative therapeutic approaches are required to target metastatic tumors selectively. In this study, we prepared AS1411 functionalized Withaferin A loaded PEGylated nanoliposomes (ALW) and investigated its therapeutic effect in B16F10 induced in pulmonary metastasis mice models. The prepared formulations' size and morphological properties were evaluated using dynamic light scattering system and Transmission electron microscope. ALW had spherical-shaped nanosized particles with a size of 118 nm and an encapsulation efficacy of 82.5 %. TEM analysis data indicated that ALW has excellent dispersibility and uniform spherical nano-size particles. ALW inhibited cell viability, and induced cell apoptosis of B16F10. In vivo, the pulmonary metastasis study in C57BL/6 mice revealed that the ALW significantly (p < 0.01) improved the encapsulated WA anti-metastatic activity and survival rate compared to WA or LW treated groups. ALW significantly (p < 0.01) downregulated the levels of IL-6, TNF-α, and IL-1ß and significantly reduced the lung collagen hydroxyproline, hexosamine, and uronic acid content in metastatic tumor bearing animals compared to WA or LW. Gene expression levels of MMPs and NF-κB were downregulated in ALW treated metastatic pulmonary tumor-bearing mice. These findings demonstrate that the AS1411 functionalized Withaferin A loaded PEGylated nanoliposomes could be a promising nanoliposomal formulation for targeting metastatic tumors.

Inhibition of tumor-specific angiogenesis by AS1411 aptamer functionalized Withaferin A loaded PEGylated nanoliposomes by targeting nucleolin.

Angiogenesis is a vital process for tumor growth and metastasis. Inhibition of angiogenesis is a promising strategy in cancer treatment. In this study, we analyzed the anti-angiogenic activity of AS1411 functionalized Withaferin A encapsulated PEGylated nanoliposomes (ALW) using both in vitro and in vivo models. AS1411 aptamer functionalized nanoliposomes are an efficient drug delivery system for carrying chemotherapeutic agents to target cancer cells, and Withaferin A (WA) is a steroidal lactone known for potent anti-angiogenic activity. ALW showed significant inhibition in the migration and tube formation of endothelial cells, which are critical events in angiogenesis. In vivo angiogenesis study using ALW showed remarkable inhibition of tumor-directed capillary formation by altered serum cytokines, VEGF, GM-CSF, and NO levels. ALW treatment downregulated the gene expression of Matrix metalloproteinase (MMP)-2, MMP-9, VEGF, NF-kB and upregulated the expression of tissue inhibitor of metalloproteinase (TIMP)-1. Our results demonstrate that ALW inhibits tumor-specific angiogenesis by gene expression of NF-κB, VEGF, MMP-2, and MMP-9. The present study shows that using ALW can offer an attractive strategy for inhibiting tumor angiogenesis.

Umbelliferone loaded PEGylated liposomes: preparation, characterization and its mitigatory effects on Dalton's ascites lymphoma development.

Umbelliferone (UB) is a phenylpropanoid-based pharmacologically active agent with promising anti-tumor activities. However, complete elucidation of its therapeutic efficacy remains challenging due to low solubility and bioavailability. The present study aimed to develop a liposomal delivery system for UB to enhance its therapeutic efficacy against Dalton's ascites lymphoma tumor model. Umbelliferone-encapsulated nanoliposomes (nLUB) were prepared using the thin-film hydration method and performed a series of characterizations to confirm successful development. The nLUB showed a particle size of 116 ± 3.2 nm with a negative surface charge and encapsulation efficiency of 78%. In vitro study results showed that nLUB treatment significantly enhanced cellular uptake and apoptosis induction in lymphoma cells compared to free UB. nLUB treatment significantly stabilized body weight, reduced tumor growth, and improved the serum biochemical and hematological parameters of experimental animals, thereby improving their overall survivability compared to an free UB. Our result indicates that nanoencapsulation enhanced the therapeutic potential of UB, which may find its way to clinical application in the near future.

The Therapeutic Effects of Withaferin A against Cancer: Overview and Updates.

Cancer is a rapidly rising health problem among the global population, and this burden causes a significant challenge for public health. Current chemotherapeutic agents have different limitations, including drug resistance and severe side effects, and it demands a robust approach to accessing promising anti-cancer therapeutics. The natural compounds have been extensively studied to identify improved therapeutic agents for cancer therapy. Withaferin A (WA) is a steroidal lactone found in Withania somnifera and possesses anti-inflammatory, antioxidant, anti-angiogenesis, and anticancer properties. Multiple studies have shown that WA treatment attenuated various cancer hallmarks by inducing apoptosis and reducing angiogenesis and metastasis with reduced side effects. WA is a promising agent for the treatment of various cancer, and it targets various signaling pathways. With recent updates, the current review highlights the therapeutic implications of WA and its molecular targets in different cancer.

NF-κB as a Potential Target for the Treatment and Prevention of Mucositis.

Mucositis is a debilitating and severe side effect of chemotherapy and radiotherapy. It is responsible for reducing the patient's quality of life and represents a significant economic burden in oncology. Currently, there is no definitive and definite treatment for this disease. Intracellular signalling pathways have provided excellent drug development resources, particularly cancer therapeutic development. In recent decades, active research has been conducted to describe the pathogenesis of mucositis and the role of nuclear factor-kappa B (NF-κB) signalling pathways in mucositis development. Insights into the mechanisms of mucositis are creating new approaches for effective targeted treatment and their success in clinical use. Several studies have concentrated on elucidating the functional significance of NF-kB activation and its signalling mechanisms in mucositis in recent decades. Also, evidence indicates that NF-κB is the primary node for the development and progression of mucositis. Its altered expression is associated with increased mucosal injury in mucositis. Hence, regulating the activation of NF-κB could be a powerful strategy for the clinical management of mucositis. Thus, this review examines the role of NF-κB as a potential therapeutic target for chemotherapy and radiation-induced mucositis therapy.

Exploring the Phytochemical Profile and Biological Activities of Clerodendrum infortunatum.

Clerodendrum infortunatum (C. infortunatum), the hill glory bower, is reputed as the prodigious treasure for Indian folk medicine. The study has focused on exploring the phytochemistry and antitumor potential of the C. infortunatum root extract in vitro and in vivo. The ethyl acetate root extract has demonstrated the highest cytotoxicity in a series of nine human tumor cell lines. Further fractionation of the same has yielded seven compounds. The structures of these compounds were confirmed with spectroscopic techniques. Considering the toxicity observed with the crude extract, cytotoxicity of these compounds was further assessed in two breast carcinoma cell lines (MCF-7[ER/PR-positive HER2-negative] and MDA-MB-231 [ER/PR/HER2-negative]) and in two cervical cancer [human papilloma virus (HPV)-negative C33A and HPV-positive SiHa] cell lines. Betulinic acid (BA) was found as the active principle contributing the cytotoxic activity, and cervical cancer cell lines documented the minimum IC50 value in 24 h. In order to validate the in vitro experimental data, we have established a xenograft model of HPV-positive cervical cancer in female NOD/SCID mice treated with BA using doxorubicin as the positive control. BA treatment gradually reduced the tumor size, maintaining healthy hematological and biochemical parameters, and improved the survival rate of tumor-bearing mice considerably. Thus, our findings suggest that the C. infortunatum root extract has a promising anticancer property against HPV-positive cervical cancer and supports its usage by traditional healers for treating cervical cancer.

Preparation and characterization of withaferin A loaded pegylated nanoliposomal formulation with high loading efficacy: In vitro and in vivo anti-tumour study.

Withaferin A (WA) is a natural steroidal lactone with promising therapeutic applications. However, its clinical application is limited due to the low bioavailability and hydrophobic nature. In this study, we had prepared PEGylated nanoliposomal withaferin A (LWA) using thin-film hydration method. Dynamic light scattering, Transmission electron microscopy, and HPLC were used to investigate the impact of prepared formulations on the size, charge, morphology, and encapsulation efficiency of the LWA. The prepared nanoliposomal system had spherical vesicles, with the mean particle size of 125 nm and had an encapsulation efficiency of 83.65% with good stability. The characterization results indicated that nanoliposomal formulation is able to improve biocompatibility and bioavailability of WA. In vitro drug release study showed that LWA had an enhanced sustained drug release effect than the free drug. In vitro studies using ascites cell lines (DLA and EAC) showed that LWA treatment could induce apoptosis in ascites cells evidenced by acridine orange/ethidium bromide, Hoechst, and Giemsa staining. In vivo tumour study revealed that LWA treatment significantly reduced tumour growth and improved survival in DLA tumour bearing mice. In vivo results further demonstrated that LWA mitigated solid tumour development by regulating Ki-67 and cyclin D1 protein expression. The overall study results reveal that nanoliposome encapsulated WA exhibits therapeutic efficacy over WA in regulating tumour development as evidenced from ascites cell apoptosis as well as experimental tumour reduction studies.

Pyrazole (1, 2-diazole) induce apoptosis in lymphoma cells by targeting BCL-2 and BCL-XL genes and mitigate murine solid tumour development by regulating cyclin-D1 and Ki-67 expression.

Pyrazole or 1,2-Diazole is a five-membered heteroaromatic ring with two nitrogen atoms which is widely used in pharmacological research and organic synthesis. Several natural and synthetic pyrazole derivatives possess anti-cancer potential and some of them have underwent clinical trials. In this aspect, an investigation into the efficiency of the pyrazole nucleus to inhibit the growth and progression of various cancer cell lines/ experimental tumours would help in giving a better clarity to the anti-cancer behaviour of pyrazole containing drugs. This paper investigates the efficiency of pyrazole against Dalton's Lymphoma Ascites (DLA) cell line. Pyrazole inhibited the growth of DLA cells in vitro by committing them towards apoptosis. In vitro results were consistent in DLA induced murine solid tumour in vivo systems. Drug-treatment improved survival, reduced tumour loads, stabilized body weights and improved the haematological and serum biochemical parameters of DLA solid tumour bearing mice, thereby improving their overall survivability. Drug administration contained the aggravation of solid tumour by targeted downregulation of Cyclin-D1 and Ki-67. In addition, the mRNA expression levels of anti-apoptotic genes, BCL-2 and BCL-XL were downregulated in solid tumours, corroborating the in vitro results that pyrazole encourage apoptotic cell death in DLA cells. The new findings establish pyrazole as a potential anti-cancer drug candidate. The results must encourage future investigations into the efficacy of the drug against various cancer types.

Edible Sword Bean Extract Induces Apoptosis in Cancer Cells In Vitro and Inhibits Ascites and Solid Tumor Development In Vivo.

Antitumor potential of edible sword bean (Canavalia gladiata (L.)) extract has been evaluated against Daltons lymphoma ascites (DLA) using in vitro and in vivo studies. Methanolic extraction was carried out and in vitro studies were performed against both DLA and A549, lung cancer cell lines. The results revealed that sword bean extract inhibited cell growth and induced apoptosis as evidenced by cytotoxic assay, Hoechst 33342 staining and acridine orange/ethidium bromide dual staining. In vivo studies performed on DLA induced solid as well as ascitic tumors models showed administration of sword bean extract (10 mg/kg B.wt.) could significantly inhibit ascitic and solid tumor development in mice. Therefore, our overall results revealed that C. gladiata treatment could significantly inhibit tumor development and induce apoptosis in tumor cells.

Mucins: Structural diversity, biosynthesis, its role in pathogenesis and as possible therapeutic targets.

Mucins are the main structural components of mucus that create a selective protective barrier for epithelial surface and also execute wide range of other physiological functions. Mucins can be classified into two types, namely secreted mucins and membrane bounded mucins. Alterations in mucin expression or glycosylation and mislocalization have been seen in various types of pathological conditions such as cancers, inflammatory bowel disease and ocular disease, which highlight the importance of mucin in maintaining homeostasis. Hence mucins can be used as attractive target for therapeutic intervention. In this review, we discuss in detail about the structural diversity of mucins; their biosynthesis; its role in pathogenesis; regulation and as possible therapeutic targets.