Targeting Aurora Kinases: A novel approach to curb the growth and chemoresistance of androgen refractory prostate cancer

Aurora Kinase (AK) based therapy targeting AK-A & B is effective against some cancers. We have explored its potential against previously unreported incurable, metastatic androgen depletion independent Prostate Cancer (ADIPC). We used androgen sensitive (AS) and ADI lines derived from Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice. The relevance of this model was unequivocally established through focussed array, quantitative PCR and western blotting studies; significantly greater alteration of genes (fold change and number) representing major cancer pathways was shown in ADI cells compared to AS lines. A marked enhancement of in vivo growth of the ADI subline showing the greatest degree of gene modulations [TRAMP C1 (TC1)-T5: TC1-T5] reflected this. In contrast to the parental AS TC1 line, TC1-T5 cells grew with 100% incidence in the prostate, as lung pseudometastases and migrated to the bone and other soft tissues. The potential involvement of AKs in this transition was indicated by the significant upregulation of AK-A/B and their downstream regulators, survivin and phosphorylated-histone H3 in TC1-T5 cells compared to TC1 cells. This led to enhanced sensitivity of TC1-T5 cells to the pan-AK inhibitor, VX680 and to significant reduction in in vivo tumour growth rates when AK-A and/or B were downregulated in TC1-T5 cells. This cell growth inhibition was markedly enhanced when both AKs were downregulated and also led to substantially greater sensitivity of these cells to docetaxel, the only chemotherapeutic with activity against ADI PC. Finally, use of VX680 with docetaxel led to impressive synergies suggesting promise for treating clinical ADI metastatic PC

Broadening the Genetic Base of Crop Brassicas by Production of New Intergeneric Hybrid

Wide hybridization between crop brassicas and their wild relatives is an important approach towards increasing the genetic variability, which can be utilised for brassica breeding programs. A new intergeneric hybrid between Erucastrum cardaminoides and Brassica oleracea var. alboglabra was produced using embryo rescue techniques.The F1 hybrid was intermediate between the male and female parent for most of the morphological characters. Cytological studies of pollen mother cells of the hybrid revealed a preponderance of univalents at metaphase I. The number of bivalents in the digenomic hybrid was lower than expected. However, the presence of trivalent and quadrivalent in cells indicated some homoeology between the two genomes and hence the possibility of introgression of genes into the cultivar. The first backcross progeny was obtained using B.oleracea var. alboglabra as the pollen parent. Further, it is being used for developing new alloplasmic lines.The intergeneric hybrid was also used as bridge species to transfer wild (E. cardaminoides) cytoplasm to B. napus and B. carinata. The new intergeneric hybrid and bridge cross hybrids produced in the present investigation have contributed towards increasing the genic and cytoplasmic variability and thus broadening the genetic base of crop brassicas

An Overview of Important Ethnomedicinal Herbs of Phyllanthus

The genus Phyllanthus consists of more than 1000 species, of which many are used as traditional medicines. The plant extracts have been used since ancient times, for treating hypertension, diabetes, hepatic, urinary, and sexual disorders, and other common ailments. Modern day scientific investigations have now confirmed pharmacognostic properties of Phyllanthus herbs. The phytochemicals attributing these medicinal properties have been identified in many of the Phyllanthus herbs. The morphologically similar herbs of Phyllanthus grow together and admixture of species during collection for manufacture of herbal medicines is quite common. Hence, along with pharmacognostic and phytochemical studies, appropriate protocols for correct identification of species are also important. As the use of these herbs as green medicines is becoming more popular, it is imperative to assess its genetic diversity and phylogenetic relatedness for future conservation strategies. This review is an attempt to present an overview of the existing studies on pharmacognostics, phytochemistry, species identification, and genetic diversity of Phyllanthus herbs and consequently (i) highlight areas where further research is needed and (ii) draw attention towards extending similar studies in underutilized but potentially important herbs such as P. maderaspatensis, P. kozhikodianus, P. rheedii, P. scabrifolius, and P. rotundifolius

Molecular chemotherapy and chemotherapy: a new front against late-stage hormone-refractory prostate cancer

Purpose: Stemming from its inherent heterogeneity, single-agent treatments are essentially ineffective against castration-resistant prostate cancer (CRPC). Thus, clinically relevant regimens that harness different modalities to maximize treatment efficacy without increasing cumulative toxicities are urgently needed. Based on this rationale, we investigated whether a novel combination of purine nucleoside phosphorylase-mediated, gene-directed enzyme-prodrug therapy (PNP-GDEPT) with docetaxel against CRPC has superior efficacy in comparison with individual treatments. Methods: The in vitro cell growth inhibition in differentially treated murine and human CRPC cell lines was established using a cell-viability assay. The extent of synergy, additivity, or antagonism between treatments was evaluated using CalcuSyn statistical analyses. The local and systemic effects of docetaxel and/or PNP-GDEPT were tested in both immunodeficient and immunocompetent mice against human and murine CRPC tumors, respectively. Subsequently, immunohistochemical analyses and an evaluation of serum cytokine and serum toxicity profiles were conducted to characterize the differential host responses to treatment. Results: The combined use of PNP-GDEPT and docetaxel led to strong synergistic cell killing in vitro. Compared with the individual modalities, a combination of the 2 led to a marked reduction in "local and distant" tumor growth in vivo, and importantly, with lowered doses and without additional toxicities. Immunomodulation was indicated by enhanced immune cell infiltration and altered serum cytokine levels. Furthermore, a lowering of T-helper type 2 cytokines, MCP-1, interleukin (IL)-4, IL-6, and IL-10 marked lower tumor burden and enhanced treatment efficacy. Conclusion: PNP-GDEPT and docetaxel are a potent combination against CRPC in immunocompetent and immunodeficient settings; these outcomes have implications of translational potential for improved treatment and management of CRPC patients