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1.  Anticancer drug FL118 is more than a survivin inhibitor: where is the Achilles’ heel of cancer? 
Can a solution be found that overcomes all chemotherapy and/or radiation resistance resulting from different genetic and epigenetic alternations in various cancer types? The answer is likely NO. However, there are two ways that may be followed to approach this goal. One way is through the use of poly-therapies that target multiple mechanisms to kill cancer cells, which is the current state of the art. This approach raises issues of high costs and/or toxic limitations, since the toxicities of each agent are often additive. This poly-pharmacy approach has not proven to be a major success, although it has proven to be superior to most current mono-pharmacy approaches. The other way to approach the goal is to find a single anticancer drug that targets multiple different treatment resistant mechanisms. In this regard, a small chemical molecule (FL118) was recently discovered by serendipity during targeted discovery of anticancer drugs using the survivin gene as a target and biomarker. FL118 was found to not only inhibit multiple antiapoptotic proteins (survivin, XIAP, cIAP2) in the inhibitor of apoptosis (IAP) family, but to also inhibit the antiapoptotic protein Mcl-1 in the Bcl-2 family, while inducing the pro-apoptotic proteins Bax and Bim expression. Importantly, inhibition of these target genes and of tumor growth by FL118 is independent of p53 status (wild type, mutant or null), although mechanisms of action may be distinct among cells with different p53 status. Therefore, FL118 may effectively control cancer that loses functional p53, in which most DNA damage drugs (if not all) show a marked lack of efficiency. Recent studies further revealed that the superior anticancer activity of FL118 is highly dependent on its primary structure and steric configuration, suggesting that FL118 may be a promising drug platform for generating novel derivatives based on its core structure. Intriguingly, although FL118 has structural similarity to irinotecan and topotecan, two FDA-approved topoisomerase 1 (Top1) inhibitors for cancer treatment, cancer cells with Top1 mutations shows little contributions of treatment resistance to FL118 antitumor activity, while strikingly increasing irinotecan and topotecan resistance. Furthermore, both irinotecan and topotecan are the efflux pump ABCG2 substrates; cancer cells with high expression of ABCG2 showed strong irinotecan and topotecan resistance. In contrast, FL118 is not an ABCG2 substrate; ABCG2 overexpression in cancer cells does not show resistance to FL118 treatment. Current evidence suggests that future studies may unravel more unexpected mechanisms of action for this unique small molecule FL118.
PMCID: PMC4065411  PMID: 24959385
Anticancer; drug; FL118; survivin inhibitor; the inhibitor of apoptosis; topoisomerase 1
2.  PCOS and obesity: insulin resistance might be a common etiology for the development of type I endometrial carcinoma 
Endometrial cancer (EC) is the most common gynecological malignancy in women and is the leading cause of cancer-related deaths worldwide. Estrogenic stimulation significantly increases endometrial cell proliferation, and both insulin resistance and hyperinsulinemia are associated with the development of EC in women. It has long been known that insulin resistance occurs in women with polycystic ovary syndrome (PCOS) and/or obesity, but one important unanswered question is whether the insulin resistance associated with PCOS and obesity is part of the etiology of the initiation and development of EC. Therefore, research efforts to understand the common and specific underlying endometrial responses to insulin resistance in women with PCOS and obesity could provide further therapeutic options for early endometrial carcinoma.
PMCID: PMC3902234  PMID: 24482740
PCOS; obesity; insulin resistance; estrogen; IGF-1; endometrial carcinoma

Results 1-5 (5)