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Doxorubicin is a prominent anticancer agent. However, its organotoxic potential has restricted its clinical use. The current study was performed to investigate the protective effect of pirfenidone and vitamin D against doxorubicin-triggered nephrotoxicity. Female albino mice (5 mice per group) were inoculated with Ehrlish scites carcinoma (EAC) cells for induction of solid tumor and treated with pirfenidone 500 mg/kg orally (p.o.) or vitamin D 0.5 μg/kg intraperitonially (i.p.), either individually or combined with single doxorubicin (15 mg/kg; i.p.) dose. Additionally, 5 mice were served as a normal group. Treatment commenced 7 days after inoculation of Ehrlich ascites carcinoma cells and lasted for 14 days. Pirfenidone and vitamin D enhanced the anti-tumor activity of doxorubicin, by decreasing tumor weight and volume. Doxorubicin increased kidney weights, creatinine, urea levels and collagen fibers deposition within renal tubules. Moreover, doxorubicin was associated with overexpression of nuclear factor-kappa B (NF-κB) and alpha-smooth muscle actin (α-SMA) as both parameters assessed by kidney immunohistochemistry. Furthermore, histological signs of large areas of interistital fibrosis and cellular infiltration were significant with sole doxorubicin treatment. Notably, doxorubicin elevated both MCP1 and TGFB1 gene expression in addition to increasing the protein expression of Smad3 and Jun N-terminal Kinase-1 (JNK1) while decreasing that of Smad7. Pirfenidone in combined with vitamin D abolished doxorubicin-evoked disturbances in the aforementioned parameters and blunted all histological alterations. Pirfenidone and vitamin D demonstrated a viable approach to suppress the nephrotoxicity initiated by doxorubicin through inhibiting the JNK1 and MCP-1 pathways. [Display omitted] [ABSTRACT FROM AUTHOR]

Different classes of phytochemicals were previously isolated from the Red Sea algae Hypnea musciformis as sterols, ketosteroids, fatty acids, and terpenoids. Herein, we report the isolation of three fatty acids—docosanoic acid 4, hexadecenoic acid 5, and alpha hydroxy octadecanoic acid 6—as well as three ceramides—A (1), B (2), and C (3)—with 9-methyl-sphinga-4,8-dienes and phytosphingosine bases. Additionally, different phytochemicals were determined using the liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry (LC-ESI-HRMS) technique. Ceramides A (1) and B (2) exhibited promising in vitro cytotoxic activity against the human breast adenocarcinoma (MCF-7) cell line when compared with doxorubicin as a positive control. Further in vivo study and biochemical estimation in a mouse model of Ehrlich ascites carcinoma (EAC) revealed that both ceramides A (1) and B (2) at doses of 1 and 2 mg/kg, respectively, significantly decreased the tumor size in mice inoculated with EAC cells. The higher dose (2 mg/kg) of ceramide B (2) particularly expressed the most pronounced decrease in serum levels of vascular endothelial growth factor -B (VEGF-B) and tumor necrosis factor-α (TNF-α) markers, as well as the expression levels of the growth factor midkine in tumor tissue relative to the EAC control group. The highest expression of apoptotic factors, p53, Bax, and caspase 3 was observed in the same group that received 2 mg/kg of ceramide B (2). Molecular docking simulations suggested that ceramides A (1) and B (2) could bind in the deep grove between the H2 helix and the Ser240-P250 loop of p53, preventing its interaction with MDM2 and leading to its accumulation. In conclusion, this study reports the cytotoxic, apoptotic, and antiangiogenic effects of ceramides isolated from the Red Sea algae Hypnea musciformis in an experimental model of EAC. [ABSTRACT FROM AUTHOR]

Natural products play a remarkable role not only in the synthesis, design, and discovery of new drugs but also as the most prominent source of drugs and bioactive substances. Adding to the search for new sources of safe innovative antitumor drugs, here we reported a phytochemical study on Pulicaria undulata which revealed promising antiangiogenic agents. Six compounds were isolated and identified as xanthoxyline (1), stigmasterol (2), oleanolic acid (3), salvigenin (4), rhamnetin (5) and dihydroquercetin-4′-methyl ether (6) using nuclear magnetic resonance (NMR) spectroscopic techniques. Compound 3 and 4 are first reported in Pulicaria genus. Both the extract and isolated compounds were evaluated for in vitro antiproliferative activity against breast cancer cell line (MCF-7). In vivo antiproliferative activity against Ehrlich's ascites carcinoma (EAC) were also assessed. The P. undulata extract and isolates showed significant reduction in tumor weight, decreased both serum vascular endothelial growth factor B (VEGF-B) levels and vascular endothelial growth factor receptor 2 (VEGFR-2) expression significantly compared to the control EAC group, suggesting an antiangiogenic activity through the inhibition of VEGF signaling. Besides, they displayed reduction in CD34 expression, confirming their antiangiogenic effect. Moreover, the potential affinity of isolated compounds to human estrogen nuclear receptor-alpha (hER-α), the most recognized modulator of VEGFR-2 expression, was virtually estimated through molecular modeling studies. The most promising activity profiles were assigned to the investigated flavonoids, compounds 4–6, as well as the alkyl-phenylketone, compound 1. Additionally, these four top active compounds showed respective high to intermediate docking scores while possessing preferential binding with hER-α critical pocket residues. Based on the provided data, these isolated compounds illustrated promising inhibitors of VEGF-stimulated angiogenesis, which could be a possible mechanism for their anticancer activity. [ABSTRACT FROM AUTHOR]

Metastasis in breast cancer is a leading cause of mortality among women in many countries. This study investigated the anti-cancer role of benzoimidazoquinazoline and benzimidazotriazin; two novel compounds that were designed, synthesized, structurally elucidated, and biologically evaluated as potent anti-angiogenic agents that act through inhibition of vascular endothelial growth factor receptor-2 (VEGFR2). Breast cancer was induced by inoculation of Ehrlich Ascites Carcinoma (EAC) cells. Seventy swiss albino mice were randomly divided into 7 groups, 10 animals each: (1) normal, (2) control EAC group, (3) cisplatin treated group, (4&5) benzoimidazoquinazoline treated (5 mg/kg and 10 mg/kg), (6&7) benzimidazotriazin treated (5 mg/kg and 10 mg/kg). The expression of miR-122 was assessed in the tumor tissue by quantitative PCR, and the VEGF level was determined in serum by ELISA. VEGFR2 and cluster of differentiation (CD)34 were assessed by immunohistochemistry. Serum ALT, AST, creatinine, and urea were measured. Treatment with benzoimidazoquinazoline and benzimidazotriazin decreased tumor weight and serum levels of VEGF, and down-regulated expression of VEGFR2 and CD34 in the tumor tissue. miR-122 was upregulated, particularly in the benzimidazotriazin (10 mg/kg) group. Relative to cisplatin, the novel compounds were less toxic to kidneys. Benzoimidazoquinazoline and benzimidazotriazin are promising anti-cancer agents that act through inhibition of angiogenesis and thus provide a new strategy for advancement of chemotherapy. Image 1 [ABSTRACT FROM AUTHOR]

Treatment of breast cancer with doxorubicin causes numerous side effects, of which cardiac fibrosis is considered the main one. This study was designed to investigate the underlying molecular mechanisms for the potential anti-fibrotic effect of pirfenidone and vitamin D against doxorubicin-induced cardiac fibrosis. Seventy mice carrying solid Ehrlich's ascites carcinoma (EAC) discs on the ventral side were treated with orally administered pirfenidone (500 mg/kg) and intraperitoneal injection of vitamin D (0.5 µg/kg) either individually or in combination with a doxorubicin (15 mg/kg; i.p.) single dose. All treatments commenced one week post-tumor inoculation and continued for 14 days. Compared to control EAC mice, the doxorubicin group showed a significant increase in heart and left ventricle weights, troponin T, and creatinine kinase serum levels. Furthermore, the doxorubicin group depicts a high expression of monocyte chemoattractant protein (MCP-1), nuclear factor-kappa B (NF-κB), transforming growth factor-beta 1 (TGF-β1), smad3, Jun N-terminal Kinase-1 (JNK1), and alpha-smooth muscle actin (α-SMA). Treatment with pirfenidone or vitamin D significantly decreased all of these parameters. Furthermore, the expression of smad7 was downregulated by doxorubicin and improved by pirfenidone or vitamin D. Furthermore, all treated groups showed a marked decrease in tumor weight and volume. Current data demonstrate that pirfenidone and vitamin D represent an attractive approach to ameliorate the cardiac fibrosis produced by doxorubicin through inhibiting both JNK1 signaling and MCP-1 inflammatory pathways, thus preserving heart function. Further, this combination demonstrated an anti-tumor effect to combat breast cancer. [ABSTRACT FROM AUTHOR]