Targeting cancer stem cells and signaling pathways by phytochemicals: Novel approach for breast cancer therapy.

Breast cancer is the most common form of cancer diagnosed in women worldwide and the second leading cause of cancer-related deaths in the USA. Despite the development of newer diagnostic methods, selective as well as targeted chemotherapies and their combinations, surgery, hormonal therapy, radiotherapy, breast cancer recurrence, metastasis and drug resistance are still the major problems for breast cancer. Emerging evidence suggest the existence of cancer stem cells (CSCs), a population of cells with the capacity to self-renew, differentiate and be capable of initiating and sustaining tumor growth. In addition, CSCs are believed to be responsible for cancer recurrence, anticancer drug resistance, and metastasis. Hence, compounds targeting breast CSCs may be better therapeutic agents for treating breast cancer and control recurrence and metastasis. Naturally occurring compounds, mainly phytochemicals have gained immense attention in recent times because of their wide safety profile, ability to target heterogeneous populations of cancer cells as well as CSCs, and their key signaling pathways. Therefore, in the present review article, we summarize our current understanding of breast CSCs and their signaling pathways, and the phytochemicals that affect these cells including curcumin, resveratrol, tea polyphenols (epigallocatechin-3-gallate, epigallocatechin), sulforaphane, genistein, indole-3-carbinol, 3, 3'-di-indolylmethane, vitamin E, retinoic acid, quercetin, parthenolide, triptolide, 6-shogaol, pterostilbene, isoliquiritigenin, celastrol, and koenimbin. These phytochemicals may serve as novel therapeutic agents for breast cancer treatment and future leads for drug development.

Inclusion complex of novel curcumin analogue CDF and ß-cyclodextrin (1:2) and its enhanced in vivo anticancer activity against pancreatic cancer.

PURPOSE: Several formulations have been proposed to improve the systemic delivery of novel cancer therapeutic compounds, including cyclodextrin derivatives. We aimed to synthesize and characterize of CDF-ß-cyclodextrin inclusion complex (1:2) (CDFCD). METHODS: The compound was characterized by Fourier transform infrared, differential scanning calorimetry, powder X-ray diffraction studies, H1 & C13 NMR studies and scanning electron microscopic analysis. Its activity was tested against multiple cancer cell lines, and in vivo bioavailability was checked. RESULTS: CDF-ß-cyclodextrin was found to lower IC(50) value by half when tested against multiple cancer cell lines. It preferentially accumulated in the pancreas, where levels of CDF-ß-cyclodextrin in mice were 10 times higher than in serum, following intravenous administration of an aqueous CDF-ß-cyclodextrin preparation. CONCLUSIONS: Novel curcumin analog CDF preferentially accumulates in the pancreas, leading to its potent anticancer activity against pancreatic cancer cells. Synthesis of such CDF-ß-cyclodextrin self-assembly is an effective strategy to enhance its bioavailability and tissue distribution, warranting further evaluation for CDF delivery in clinical settings for treatment of human malignancies.

Antioxidant, antinociceptive and anti-inflammatory activities of atorvastatin and rosuvastatin in various experimental models.

The present study was planned to investigate the antioxidant, antinociceptive, and anti-inflammatory activities of atorvastatin and rosuvastatin (1, 3 and 10 mg/kg, p.o.) in various animal models. The antinociceptive effect was assessed by chemically- (formalin, acetic acid) and thermally- (hot plate) induced nociception, while anti-inflammatory effect was evaluated using carrageenan-, formaldehyde-induced paw oedema and cotton pellet-induced granuloma. The effect of atorvastatin and rosuvastatin on liver antioxidant enzymes like superoxide dismutase, glutathione, LPO, CAT along with the effect on lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) was evaluated in the cotton pellet-induced granuloma model. Atorvastatin and rosuvastatin showed significant decrease (p < 0.05) in carrageenan- and formaldehyde-induced rat paw oedema and reduced granuloma formation in the cotton pellet-induced granuloma method (p < 0.01) while the levels of LDH and ALP were also significantly decreased (p < 0.05). The liver antioxidant enzyme levels were found to be restored (p < 0.05). Atorvastatin and rosuvastatin also showed antinociceptive activities (p < 0.05 and p < 0.01) in the acetic acid- and formalin-induced nociception in mice, while there was no significant activity in the hot plate method. The present findings suggest that atorvastatin and rosuvastatin possess dose-dependent antioxidant, analgesic, and anti-inflammatory activities.

Bitter melon: a panacea for inflammation and cancer.

Nature is a rich source of medicinal plants and their products that are useful for treatment of various diseases and disorders. Momordica charantia, commonly known as bitter melon or bitter gourd, is one of such plants known for its biological activities used in traditional system of medicines. This plant is cultivated in all over the world, including tropical areas of Asia, Amazon, east Africa, and the Caribbean and used as a vegetable as well as folk medicine. All parts of the plant, including the fruit, are commonly consumed and cooked with different vegetables, stir-fried, stuffed or used in small quantities in soups or beans to give a slightly bitter flavor and taste. The plant is reported to possess anti-oxidant, anti-inflammatory, anti-cancer, anti-diabetic, anti-bacterial, anti-obesity, and immunomodulatory activities. The plant extract inhibits cancer cell growth by inducing apoptosis, cell cycle arrest, autophagy and inhibiting cancer stem cells. The plant is rich in bioactive chemical constituents like cucurbitane type triterpenoids, triterpene glycosides, phenolic acids, flavonoids, essential oils, saponins, fatty acids, and proteins. Some of the isolated compounds (Kuguacin J, Karaviloside XI, Kuguaglycoside C, Momordicoside Q-U, Charantin, α-eleostearic acid) and proteins (α-Momorcharin, RNase MC2, MAP30) possess potent biological activity. In the present review, we are summarizing the anti-oxidant, anti-inflammatory, and anti-cancer activities of Momordica charantia along with a short account of important chemical constituents, providing a basis for establishing detail biological activities of the plant and developing novel drug molecules based on the active chemical constituents.

Quinomycin A targets Notch signaling pathway in pancreatic cancer stem cells.

Cancer stem cells (CSCs) appear to explain many aspects of the neoplastic evolution of tumors and likely account for enhanced therapeutic resistance following treatment. Dysregulated Notch signaling, which affects CSCs plays an important role in pancreatic cancer progression. We have determined the ability of Quinomycin to inhibit CSCs and the Notch signaling pathway. Quinomycin treatment resulted in significant inhibition of proliferation and colony formation in pancreatic cancer cell lines, but not in normal pancreatic epithelial cells. Moreover, Quinomycin affected pancreatosphere formation. The compound also decreased the expression of CSC marker proteins DCLK1, CD44, CD24 and EPCAM. In addition, flow cytometry studies demonstrated that Quinomycin reduced the number of DCLK1+ cells. Furthermore, levels of Notch 1-4 receptors, their ligands Jagged1, Jagged2, DLL1, DLL3, DLL4 and the downstream target protein Hes-1 were reduced. The γ-secretase complex proteins, Presenilin 1, Nicastrin, Pen2, and APH-1, required for Notch activation also exhibited decreased expression. Ectopic expression of the Notch Intracellular Domain (NICD) partially rescued the cells from Quinomycin mediated growth suppression. To determine the effect of Quinomycin on tumor growth in vivo, nude mice carrying tumor xenografts were administered Quinomycin intraperitoneally every day for 21 days. Treatment with the compound significantly inhibited tumor xenograft growth, coupled with significant reduction in the expression of CSC markers and Notch signaling proteins. Together, these data suggest that Quinomycin is a potent inhibitor of pancreatic cancer that targets the stem cells by inhibiting Notch signaling proteins.

Perspectives on medicinal properties of benzoquinone compounds.

Benzoquinones are class of natural quinones found chiefly in higher plants, fungi, bacteria and animal kingdom. They are involved in important biological functions such as bioenergetic transport, oxidative phosphorylation and electron transport processes. In recent years it has become increasingly clear that some of them possess potent antioxidant, anti-inflammatory and anticancer activities. There is clearly a common thread running through these activities and there have been a large number of studies carried out to unravel the mechanisms of these activities. In the present review we have provided a brief account of these studies especially covering these aspects. Although antioxidant potentials of these compounds constitute the basis of their biological activities its nature and scope is dictated by many microscopic biological environments. One of the important advantages offered by these compounds is the ease with which they can be synthesized and chemically manipulated. This can easily provide impetus for further research in developing some potentially useful drug molecules.

Transition metal complexes of 3-aryl-2-substituted 1,2-dihydroquinazolin-4(3H)-one derivatives: new class of analgesic and anti-inflammatory agents.

Five-coordinate, neutral transition metal complexes of newly designed pyridine-2-ethyl-(3-carboxylideneamino)-3-(2-phenyl)-1,2-dihydroquinazolin-4(3H)-one (L) were synthesized and characterized. The structure of ligand is confirmed by single crystal X-ray diffraction studies. The compounds were evaluated for the anti-inflammatory activity by carrageenan-induced rat paw edema model while their analgesic activity was determined by acetic acid-induced writhing test in mice wherein the transition metal complexes were found to be more active than the free ligand.