Ali M. Mahmoud

Resveratrol enhances the cytotoxic profile of docetaxel and doxorubicin in solid tumour cell lines in vitro

Objectives:  Resveratrol, with its robust antioxidant activity, has frequently been suggested as potentially having activity in cancer prevention and some recent reports have indicated that it has cancer treatment potential for several types of neoplasia. It has been found to block p‐glycoprotein and to protect against several chemotherapeutic agents’ side effects. In this study, we assessed interactive characteristics of resveratrol with docetaxel and doxorubicin and further investigated molecular bases of this interaction in cells of three different solid tumour lines (MCF‐7, HeLa and HepG2).

Eichhornia crassipes (Mart) solms: From water parasite to potential medicinal remedy

Water hyacinth, Eichhornia crassipes (Mart) Solms, originating in the amazonian basin, is a warm water aquatic plant. Water hyacinth is considered one of the most productive plants on earth and, accordingly, is considered one of the top 10 world’s worst weeds. Water hyacinth spread to other tropical and subtropical regions by humans. It invaded about 62 countries in Africa, Asia and North America, and propagated extremely serious ecological, economical and social problems in the region between 40 degrees north and 45 degrees south. The dense weed of water hyacinth forms dense monocultures that can threaten local native species diversity and change the physical and chemical aquatic environment, thus altering ecosystem structure and function by disrupting food chains and nutrient cycling. We have separated and identified nine active fractions from water hyacinth and showed their promising therapeutic activities. Several compounds (alkaloid, phthalate derivatives, propanoid and phenyl derivatives) were identified in the extract of water hyacinth.

Anti-cancer characteristics of mevinolin against three different solid tumor cell lines was not solely p53-dependent

Mevinolin (MVN) has been used clinically for the treatment of hypercholesterolemia with very good tolerance by patients. Based on epidemiological evidences, MVN was suggested strongly for the treatment of neoplasia. Early experimental trials suggested the mixed apoptotic/necrotic cell death pathway was activated in response to MVN exposure. Herein, the cytotoxic profile of MVN was evaluated, compared to the robust and frequently used anti-cancer drug doxorubicin (DOX), against breast (MCF-7), cervical (HeLa) and liver (HepG2) transformed cell lines. MVN was showed comparable results in cytotoxic profile with DOX in all tested solid tumor cell lines. In addition, the MVN-induced cytotoxicity was inferred to be multi-factorial and not solely dependent on p53 expression. It was concluded that molecular and genetic assessment of MVN-induced cell death would be useful for developing cancer therapeutic treatments.

Effects of plant-derived anti-leukemic drugs on individualized leukemic cell population profiles in Egyptian patients

Leukemias are a group of cancer types that originate from blood-forming tissues. In this disease, an abnormally large number of immature white blood cells is produced by the bone marrow. The relationship between treatments with plant-derived drugs and leukemia-associated immunophenotypes (LAIPs) of clinically isolated leukemia cells has yet to be established. The aim of the present study was to develop a preliminary clinical prognostic map for commonly expressed LAIPs in patients clinically diagnosed with leukemia, as well as to assess the potential involvement of LAIPs in the response rate to 10 natural products of plant origin. An increased expression of LAIPs, including CD4, CD14, CD33 and CD34, was considered a surrogate marker of the desired response of leukemia cells to treatment with plant-derived drugs. By contrast, the increased expression of the LAIPs, MPO and DR, was associated with poor prognostic outcomes following treatment with the plant-derived drugs. The results showed that 5 of the 10 plant-derived drugs tested induced the expression of several desirable LAIPs biomarkers. These findings clearly highlight the potential treatment efficacy of certain plant-derived drugs against leukemic cell types.

Transcriptional profiling of breast cancer cells in response to mevinolin: Evidence of cell cycle arrest, DNA degradation and apoptosis

The merging of high-throughput gene expression techniques, such as microarray, in the screening of natural products as anticancer agents, is considered the optimal solution for gaining a better understanding of the intervention mechanism. Red yeast rice (RYR), a Chinese dietary product, contains a mixture of hypocholesterolemia agents such as statins. Typically, statins have this effect via the inhibition of HMG-CoA reductase, the key enzyme in the biosynthesis of cholesterol. Recently, statins have been shown to exhibit various beneficial antineoplastic properties through the disruption of tumor angiogenesis and metastatic processes. Mevinolin (MVN) is a member of statins and is abundantly present in RYR. Early experimental trials suggested that the mixed apoptotic/necrotic cell death pathway is activated in response to MVN exposure. In the current study, the cytotoxic profile of MVN was evaluated against MCF-7, a breast cancer-derived cell line. The obtained results indicated that MVN-induced cytotoxicity is multi-factorial involving several regulatory pathways in the cytotoxic effects of MVN on breast cancer cell lines. In addition, MVN-induced transcript abundance profiles inferred from microarrays showed significant changes in some key cell processes. The changes were predicted to induce cell cycle arrest and reactive oxygen species generation but inhibit DNA repair and cell proliferation. This MVN-mediated multi-factorial stress triggered specific programmed cell death (apoptosis) and DNA degradation responses in breast cancer cells. Taken together, the observed MVN-induced effects underscore the potential of this ubiquitous natural compound as a selective anticancer activity, with broad safety margins and low cost compared to benchmarked traditional synthetic chemotherapeutic agents. Additionally, the data support further pre-clinical and clinical evaluations of MVN as a novel strategy to combat breast cancer and overcome drug resistance.

Abstract 1698: Resveratrol potentiates the cytotoxic profile of docetaxel and doxorubicin via inhibiting the activity and expression of p-glycoprotein molecules

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL P-glycoprotein is membrane protein highly abundant in tumor cells which facilitate the effluxes of several chemotherapeutic agents to the extracellular compartment. Several P-glycoprotein blockers of synthetic origin were suggested as adjuvant therapy for cancer; however, manifested several toxic side effects. Resveratrol was found to block p-glycoprotein with potential use as adjuvant therapy for several p-glycoprotein substrates such as docetaxel and doxorubicin. Herein, we have assessed the interactive characteristics of resveratrol with docetaxel and doxorubicin and further investigated the molecular bases of this interaction in three different solid tumor cell lines (MCF-7, HeLa and HepG2). Resveratrol per se was found to possess anti-cancer properties; however with relatively low potency in all tested cell lines (IC50 ranges from 8.0 to 19.1µg/ml). Doxorubicin and docetaxel showed IC50‘s ranged from 0.28 to 0.42 µg/ml and from 22.3 to 67.1 ng/ml, respectively. Resveratrol combination with doxorubicin and docetaxel significantly increased the potencies of both chemotherapeutic agents showing IC50‘s ranging from 0.07 to 0.2 µg/ml and from 6.2 to 45.7 ng/ml, respectively. The combination index showed synergistic interaction between resveratrol and doxorubicin or docetaxel in MCF-7 cell line, while additive interaction in HeLa and Hep-G2 cell lines. Real time PCR revealed that the expression of BAX and BcL2 were simultaneously elevated due to combination of resveratrol with doxorubicin or docetaxel in all tested cell lines while p-53 showed marginal elevation in MCF-7 and HepG2 cell lines. The p-glycoprotein efflux activity was significantly inhibited with subsequent accumulation of p-glycoprotein substrate within the intracellular compartment of all tested cell lines. Also the expression level of mdr1 gene was down regulated after resveratrol combination with doxorubicin or docetaxel in all tested cell lines. In conclusion, resveratrol potentiates the anti-cancer effects of doxorubicin and docetaxel via increasing their intracellular level due to p-glycoprotein activity inhibition and down regulation of mdr1 gene. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1698. doi:10.1158/1538-7445.AM2011-1698