RESUMEN
Triple-negative breast cancer (TNBC) has limited treatment options and the worst prognosis among all types of breast cancer. We describe two prodrugs, namely, CWB-20145 (1) and its methyl analogue FAN-NM-CH3 (2) that reduced the size of TNBC-derived tumors. The DNA cross-linking of nitrogen mustard prodrugs 1 and 2 was superior to that of chlorambucil and melphalan once activated in the presence of H2O2. The cellular toxicity of 1 and 2 was demonstrated in seven human cancer cell lines. The TNBC cell line MDA-MB-468 was particularly sensitive toward 1 and 2. Compound 2 was 10 times more cytotoxic than chlorambucil and 16 times more active than melphalan. An evaluation of the gene expression demonstrated an upregulation of the tumor suppressor genes p53 and p21 supporting a transcriptional mechanism of a reduced tumor growth. Pharmacokinetic studies with 1 showed a rapid conversion of the prodrug. The introduction of a methyl group generated 2 with an increased half-life. An in vivo toxicity study in mice demonstrated that both prodrugs were less toxic than chlorambucil. Compounds 1 and 2 reduced tumor growth with an inhibition rate of more than 90% in athymic nude mice xenografted with MDA-MB-468 cells. Together, the in vivo investigations demonstrated that treatment with 1 and 2 suppressed tumor growth without affecting normal tissues in mice. These phenylboronic acid nitrogen mustard prodrugs represent promising drug candidates for the treatment of TNBC. However, the mechanisms underlying their superior in vivo activity and selectivity as well as the correlation between H2O2 level and in vivo efficacy are not yet fully understood.
RESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: There is very limited information regarding plants used by traditional healers in Bandarban Hill Tracts (BHT), Bangladesh for treating general as well as complex ailments. Current study provides significant ethnopharmacological information, both qualitative and quantitative on medical plants in BHT. Aim of the study This study aimed to collect, analyze and evaluate the rich ethnopharmacologic knowledge on medicinal plants in Thanchi, BHT and attempted to identify the important species used in traditional medicine. Further analysis was done by comparison of the traditional medicinal use of the plants with the available scientific literature data. MATERIALS AND METHODS: The field survey was carried out in a period of several years in Thanchi upazilla of Bandarban districts, Bangladesh. A total of 53 Traditional Health Practitioners (THPs) were interviewed through open-ended and semi structured questionnaire. The collected data were analyzed qualitatively and quantitatively. This ethnomedicinal knowledge was compared against the available scientific literature for reports of related uses and studies of phytochemical compounds responsible for respective ailments. RESULTS: A total of 84 species of plants, mostly herbs, belonging to 42 families were identified for the treatment of 70 types of ailments. These ailments were categorized into 16 categories. Leaves were the most frequently used plant parts and juice is the mode of preparation of major portions of the plant species. The most common mode of administration was oral ingestion and topical application. Informant consensus factor (Fic) values of the present study reflected the high agreement in the use of plants in the treatment of digestive system and respiratory system disorders among the informants. Diseases of the digestive system had highest use-reports and 3 species of plants, namely Centella asiatica (L.) Urban. (dysentery), Justicia gendarussa L. (asthma) and Ocimum tenuiflorum L. (coughing) had the highest fidelity level (FL) of 100%. Clerodendrum viscosum Vent., Achyranthes aspera L and Justicia gendarussa L. showed the highest relative importance (RI) value of 1.86. According to use value (UV) the most important species were Ocimum tenuiflorum L. (2.24) and Achyranthes aspera L. (2.15). CONCLUSION: Priority should be given for further phytochemical investigation to plants that scored highest FL, Fic, UV or RI values, as such values could be considered as good indicator of prospective plants for discovering new drugs. Since knowledge regarding traditional medicine being vulnerable day by day so traditional medicine in school curricula should be incorporated so that younger people could appreciate its usefulness. Also counseling of THPs and gardening of medicinal plants should be taken into consideration immediately in order to smooth continuance and extension of traditional medical knowledge and practice for ensuring safe and effective therapy.
