Natural products targeting cancer stem cells: Implications for cancer chemoprevention and therapeutics.

Cancer, being the leading cause of death in the globe, has been one of the major thrust areas of research worldwide. In a new paradigm about neoplastic transformations, the initiation and recurrence of disease is attributed to few mutated cells in bulk of tumor called cancer stem cells (CSCs). CSCs have capacity of self-renewal and differentiation, which are known for resistance to radio and chemotherapy leading to recurrence of the disease even after treatment. Most of traditional drugs implicated in cancer therapy targeting primary tumors have substantial toxicity to the physiological system and have not been efficient in targeting these CSCs leading to poor prognosis. Targeting these CSCs in bulk of tumor might be novel strategy for cancer chemoprevention and therapeutics. Diet-derived interventions and diverse natural products are known to target these CSCs and related signaling pathways, namely, Wnt, Notch, and Hedgehog pathways, which are implicated for CSC self-renewal. PRACTICAL APPLICATIONS: Cancer remains a global challenge even in this century. Poor prognosis, survival rate, and recurrence of the disease have been the major concerns in traditional cancer therapy regimes. Targeting cancer stem cells might be novel strategy for elimination and cure of the chronic disease as they are known to modulate all stages of carcinogenesis and responsible for recurrence and resistance to chemotherapy and radiotherapy. The evidence support that natural products might inhibit, delay, or reverse the process of tumorigenesis and modulate the different signaling pathways implicated for cancer stem cells self-renewal and differentiation. Natural products have minimal toxicity compared to traditional cancer therapy drugs since they have long been utilized in our food habits without any major side effects reported. Thus, targeting cancer stem cells with natural product might be a novel strategy for drug development in cancer chemoprevention and therapeutics.

Design, synthesis and characterization of some bioactive conjugates of curcumin with glycine, glutamic acid, valine and demethylenated piperic acid and study of their antimicrobial and antiproliferative properties.

The monoesters of curcumin, a symmetric diphenol with valine and glycine have been prepared by a novel solid phase synthesis and its diesters with valine, glutamic acid and demethylenated piperic acid have been prepared by solution phase method. The assessment of their antimicrobial and anticancer (antiproliferative) activities suggested that diesters of curcumin are relatively more active than curcumin itself due to their increased solubility, slow metabolism and better cellular uptake. Furthermore, significant observation was that monoesters of curcumin have even better antimicrobial activity than their corresponding diesters, emphasizing the role of free phenolic group. The conjugate of curcumin with demethylenated piperic acid in which methylenedioxy ring was open also shows enhanced activity than the corresponding piperic acid conjugate, emphasizing the role of free phenolics in the transport or in the binding processes.

Immunomodulatory and therapeutic activity of curcumin.

Inflammation is a disease of vigorous uncontrolled activated immune responses. Overwhelming reports have suggested that the modulation of immune responses by curcumin plays a dominant role in the treatment of inflammation and metabolic diseases. Observations from both in-vitro and in-vivo studies have provided strong evidence towards the therapeutic potential of curcumin. These studies have also identified a plethora of biological targets and intricate mechanisms of action that characterize curcumin as a potent 'drug' for numerous ailments. During inflammation the functional influence of lymphocytes and the related cross-talk can be modulated by curcumin to achieve the desired immune status against diseases. This review describes the regulation of immune responses by curcumin and effectiveness of curcumin in treatment of diseases of diverse nature.

Lipoglycans contribute to innate immune detection of mycobacteria.

Innate immune recognition is based on the detection, by pattern recognition receptors (PRRs), of molecular structures that are unique to microorganisms. Lipoglycans are macromolecules specific to the cell envelope of mycobacteria and related genera. They have been described to be ligands, as purified molecules, of several PRRs, including the C-type lectins Mannose Receptor and DC-SIGN, as well as TLR2. However, whether they are really sensed by these receptors in the context of a bacterium infection remains unclear. To address this question, we used the model organism Mycobacterium smegmatis to generate mutants altered for the production of lipoglycans. Since their biosynthesis cannot be fully abrogated, we manipulated the biosynthesis pathway of GDP-Mannose to obtain some strains with either augmented (∼1.7 fold) or reduced (∼2 fold) production of lipoglycans. Interestingly, infection experiments demonstrated a direct correlation between the amount of lipoglycans in the bacterial cell envelope on one hand and the magnitude of innate immune signaling in TLR2 reporter cells, monocyte/macrophage THP-1 cell line and human dendritic cells, as revealed by NF-κB activation and IL-8 production, on the other hand. These data establish that lipoglycans are bona fide Microbe-Associated Molecular Patterns contributing to innate immune detection of mycobacteria, via TLR2 among other PRRs.