Breast Cancer research studies for holistic treatments

Background:
Given the importance of complementary and alternative medicine (CAM) to cancer patients, there is an increasing need to learn more about possible interactions between CAM and anticancer drugs. Mistletoe (Viscum album L.) belongs to the medicinal herbs that are used as supportive care during chemotherapy. In the in vitro study presented here the effect of standardized mistletoe preparations on the cytostatic and cytotoxic activity of several common conventional chemotherapeutic drugs was investigated using different cancer cell lines.
METHODS:
Human breast carcinoma cell lines HCC1937 and HCC1143 were treated with doxorubicin hydrochloride, pancreas adenocarcinoma cell line PA-TU-8902 with gemcitabine hydrochloride, prostate carcinoma cell line DU145 with docetaxel and mitoxantrone hydrochloride and lung carcinoma cell line NCI-H460 was treated with docetaxel and cisplatin. Each dose of the respective chemotherapeutic drug was combined with Viscum album extract (VAE) in clinically relevant concentrations and proliferation and apoptosis were measured.
Results:
VAE did not inhibit chemotherapy induced cytostasis and cytotoxicity in any of our experimental settings. At higher concentrations VAE showed an additive inhibitory effect. CONCLUSIONS: Our in vitro results suggest that no risk of safety by herb drug interactions has to be expected from the exposition of cancer cells to chemotherapeutic drugs and VAE simultaneously.

Hormonal therapy is the mainstay of adjuvant treatment for women with early-stage estrogen receptor-positive breast cancer. Recently, the aromatase inhibitors have moved to the forefront of adjuvant hormonal therapy, however, the adverse effects of these agents are not yet fully understood. It is generally accepted that tamoxifen, but not the aromatase inhibitors, is associated with an increased risk of thrombosis in women with breast cancer. Studies comparing aromatase inhibitors to tamoxifen in the adjuvant setting have reported a lower rate of venous thromboembolism with the aromatase inhibitors, yet the incidence of venous thromboembolism with these new agents is higher than that expected in the general population. Here we report a case of acute bilateral pulmonary emboli occurring while on adjuvant aromatase inhibitor therapy with anastrozole, and review the literature on the incidence of venous thromboembolism during the use of aromatase inhibitors in the adjuvant setting.

Background:
Actin cytoskeleton is involved in actin-based cell adhesion, cell motility, and matrix metalloproteinases(MMPs) MMP2, MMP9, MMP11 and MMP14 are responsible for cell invasion in breast cancer metastasis. The dietary intake of lignan from flax seed gets converted to enterolactone (EL) and enterodiol in the human system. Here we show that the enterolactone has a very significant anti-metastatic activity as demonstrated by its ability to inhibit adhesion and invasion and migration in MCF-7 and MDA MB231 cell lines. MATERIALS AND
METHODS:
Migration inhibition assay, actin-based cell motility assay along with reverse transcriptase polymerase chain reaction (RT-PCR) for MMP2, MMP9, MMP11 and MMP14 genes were performed in MCF-7 and MDA MB 231 cell lines.
Results:
Enterolactone seems to inhibit actin-based cell motility as evidenced by confocal imaging and photo documentation of cell migration assay. The results are supported by the observation that the enterolactone in vitro significantly down-regulates the metastasis-related metalloproteinases MMP2, MMP9 and MMP14 gene expressions. No significant alteration in the MMP11 gene expression was found. CONCLUSIONS: Therefore we suggest that the anti-metastatic activity of EL is attributed to its ability to inhibit cell adhesion, cell invasion and cell motility. EL affects normal filopodia and lamellipodia structures, polymerization of actin filaments at their leading edges and thereby inhibits actin-based cell adhesion and cell motility. The process involves multiple force-generating mechanisms of actin filaments i.e. protrusion, traction, deadhesion and tail-retraction. By down-regulating the metastasis-related MMP2, MMP9 and MMP14 gene expressions, EL may be responsible for cell invasion step of metastasis.

Pterostilbene, a dimethyl ester derivative of resveratrol, may act as an cytotoxic and hence as an anti-cancer agent. The present study was conducted to test the anti-cancer activity of pterostilbene purified from Pterocarpus marsupium on breast (MCF-7) and prostate (PC3) cancer cell lines. The purified pterostilbene was found to cause apoptosis in both the cell lines, which was marked by DNA fragmentation, formation of apoptotic bodies and membrane distortions. Apoptosis probably was due to the production of reactive oxygen species in MCF-7 and nitric oxide over production in PC3 cells. Even the drug detoxifying anti-oxidant enzymes could not nullify the effect of pterostilbene as required by the cancer cells for survival. Pterostilbene was found to inhibit the cell proliferating factors like Akt, Bcl-2 and induced the mitochondrial apoptotic signals like Bax, and the series of caspases. It also inhibited Matrix metalloproteinase 9 (MMP9) and alpha-methylacyl-CoA recemase (AMACR), two very well known metastasis inducers. In conclusion, pterostilbene has multiple target sites to induce apoptosis. Hence, after proper validation it can be used as a potential agent for the cure of breast and prostate cancer.

Resveratrol, a constituent of grapes and other food products, has been shown to prevent carcinogenesis in murine models. We report here that resveratrol induces apoptotic cell death in HL60 human leukemia cell line. Resveratrol-treated tumor cells exhibit a dose-dependent increase in externalization of inner membrane phosphatidylserine and in cellular content of subdiploid DNA, indicating loss of membrane phospholipid asymmetry and DNA fragmentation. Resveratrol-induced cell death is mediated by intracellular caspases as observed by the dose-dependent increase in proteolytic cleavage of caspase substrate poly (ADP-ribose) polymerase (PARP) and the ability of caspase inhibitors to block resveratrol cytotoxicity. We also show that resveratrol treatment enhances CD95L expression on HL60 cells, as well as T47D breast carcinoma cells, and that resveratrol-mediated cell death is specifically CD95-signaling dependent. On the contrary, resveratrol treatment of normal human peripheral blood lymphocytes (PBLs) does not affect cell survival for up to 72 hours, which correlates with the absence of a significant change in either CD95 or CD95L expression on treated PBLs. These data show specific involvement of the CD95-CD95L system in the anti-cancer activity of resveratrol and highlight the chemotherapeutic potential of this natural product, in addition to its recently reported chemopreventive activity.

Fisetin can be found in a wide variety of plants and possesses strong efficacy against many cancers. 17?-Estradiol (E2) is hydrolyzed to 4-hydroxy-E2 (4-OHE2) via cytochrome P450 (CYP) 1B1 in vivo. In estrogen target tissues including the mammary gland, ovaries, and uterus, CYP1B1 is highly expressed, and 4-OHE2 is predominantly formed in cancerous tissues. Herein, we investigated the inhibitory activity of fisetin and flavone against CYP1B1 using estrogen E2 as substrate in vitro to reveal structure-activity relationship between structure of flavonoids and inhibition. The results showed that fisetin possessed inhibitory effect on CYP1B1 activity. Compared with flavone, the inhibition of fisetin was stronger. The Vmax and Ki values were 1.950±0.157 pmol/?g protein/min and 4.925±0.689 nM for fisetin and 2.277±0.231pmol/?g protein/min and 9.148±2.150 nM for flavone, respectively. By kinetic analyses, both fisetin and flavone displayed mixed inhibition. Taken together the data suggested that fisetin is able to inhibit the formation of carcinogenic 4-OHE2 from E2, which reveals one of its anti-cancer mechanisms and helps to reveal the relationship between the structure of flavonoids and the inhibition CYP1B1 for discovering new drugs in cancer therapy and prevention.