RESUMEN

Cellular transformation is a major event that helps cells to evade apoptosis, genomic instability checkpoints, and immune surveillance to initiate tumorigenesis and to promote progression by cancer stem cell expansion. However, the key molecular players that govern cellular transformation and ways to target cellular transformation for therapy are poorly understood to date. Here we draw key evidences from the literature on K-Ras-driven cellular transformation in the context of apoptosis to shed light on the key players that are required for cellular transformation and explain how aiming p53 could be useful to target cellular transformation. The defects in key apoptosis regulators such as p53, Bax, and Bak lead to apoptosis evasion, cellular transformation, and genomic instability to further lead to stemness, tumorigenesis, and metastasis via c-Myc-dependent transcription. Therefore enabling key apoptotic checkpoints in combination with K-Ras inhibitors will be a promising therapeutic target in cancer therapy.

RESUMEN

It has been reported that Breast Cancer Susceptibility gene-1 & 2 (BRCA1 & 2 are potential molecular targets for chemoprevention by isoflavone genistein (4' 5, 7-trihydroxy isoflavone), in breast and prostate cancer cells. It is also known that BRCA1 has inhibitory activity on estrogen receptor-alpha and genistein's action on cells is mainly through modulation of estrogen receptor activity. The action of genistein with respect to BRCA1 status in ovarian cancer cells has not been reported so far. Therefore in this study, we analyzed the action of genistein on BRCA1 antisense blocked (AS4) and unblocked (NEO) BG-1 ovarian cancer cells. We found that genistein induced comparable cytotoxic effect in both AS4 and NEO cells, but through different pathways. We found that genistein induces caspase 8 dependent apoptotic pathway in NEO cells. Genistein inhibits estrogen receptor-alpha and activates BARD1 in BRCA1 blocked cells and induces estrogen receptor-beta and FAS in presence of BRCA1. It can be concluded that even though there is no difference in the extent of cell death or apoptosis, the molecular mechanism of action of genistein in inducing apoptosis is different in BRCA1 blocked and unblocked cells. This could partially explain the beneficial effects of genistein in both wild type and mutated BRCA1 estrogen receptor positive tumors.

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RESUMEN

Curcumin (1, 7-bis (4-hydroxyl-3-methoxyphenyl)-1, 6 heptadiene-3, 5-dione) is a potent natural anti oxidant and anti-inflammatory agent, which mediates its effects mainly by inhibiting the activity of enzymes like cyclooxygenase, lipooxygenases and phospholipase A2. Here we examined the possibility of curcumin affecting the production of matrix metalloproteinases (MMPs) by peripheral blood mononuclear cells (PBMCs), which play an important role in inflammation. Zymographic analysis and ELISA showed that curcumin significantly inhibited the activity and level of MMPs produced by PBMCs isolated from human and inflammation-induced rabbit in a concentration dependent manner. The administration of curcumin to inflammation-induced rabbits also caused downregulation of MMP-9. Kinetic analysis showed that the effect of curcumin was a delayed one indicating inhibition of de novo protein synthesis. RT-PCR and immunoblot analysis showed inhibition of the production of MMP-9 mRNA and protein respectively by human PBMCs, which were activated in vitro by Artocarpus Lakoocha agglutinin (ALA) lectin. EMSA and super shift showed activation of classical NFkappaB in in vitro activated PBMCs and treatment with curcumin inhibited activation of NFkappaB. Immunoblot analysis suggested that ALA-induced activation of NFkappaB leading to the upregulation of MMP-9 was due to the degradation of IkappaB-alpha. Curcumin inhibited the degradation of IkappaB-alpha, which inhibited the ALA mediated activation of NFkappaB and upregulation of MMP-9. These results indicated that anti-inflammatory effect of curcumin also involves inhibition of the production of MMP-9 in PBMCs.

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