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A novel, nontoxic iron chelator, super-polyphenol, effectively induces apoptosis in human cancer cell lines.

ABSTRACT: Iron chelation therapy is the main treatment for iron overload disease. Iron chelators were recently reported to be useful for cancer therapy; however, they cause side effects that make them difficult to use in some cancer patients. Thus, a novel oral iron chelator, super-polyphenol (SP), was developed for cancer therapy to decrease the side effects. SP is either water soluble or insoluble, and has different isoforms according to the number of side chains. Of these isoforms, water-soluble SP6 and SP10 appear to be the best candidates, as they have the strongest chelating abilities. In this study, we focused on the usefulness and safety of SP6 and SP10 as anti-cancer drugs, and examined their anti-cancer effects and toxicity. The results showed that SP6 and SP10 inhibited cancer cell proliferation by inducing apoptosis in HCT116, HSC-2, A549, and MCF-7 cancer cells. SP10 also inhibited tumor growth in an HCT116 xenograft model. SP6 and SP10 had no acute toxicities. An intravenous injection test revealed that SP6 and SP10 had better safety profiles than the iron chelator deferoxamine. In conclusion, SP is a novel oral iron chelator with anti-cancer effects and few adverse side effects. This is the first report of SP in the literature.

SUBMITTER: Ohara T

PROVIDER: S-EPMC6132348 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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A novel, nontoxic iron chelator, super-polyphenol, effectively induces apoptosis in human cancer cell lines.

Ohara Toshiaki T Tomono Yasuko Y Boyi Xing X Yingfu Sun S Omori Kazuhiro K Matsukawa Akihiro A

Oncotarget 20180828 67

Iron chelation therapy is the main treatment for iron overload disease. Iron chelators were recently reported to be useful for cancer therapy; however, they cause side effects that make them difficult to use in some cancer patients. Thus, a novel oral iron chelator, super-polyphenol (SP), was developed for cancer therapy to decrease the side effects. SP is either water soluble or insoluble, and has different isoforms according to the number of side chains. Of these isoforms, water-soluble SP6 an ...[more]

PMID: 30214682

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Project description:Iron is an essential micronutrient due to its involvement in many cellular processes including DNA replication and OXPHOS. Tumors overexpress iron metabolism linked proteins which allow for iron accumulation driving high levels of proliferation. Our group has designed novel iron chelator SK4 which targets cancer's "iron addiction." SK4 comprises of two key moieties: an iron chelation moiety responsible for cytotoxicity and an amino acid moiety which allows entry through amino acid transporter LAT1. We selected LAT1 as a route of entry as it is commonly overexpressed in malignant tumors. SK4 has previously demonstrated promising results in an in vitro model for melanoma. We hypothesized SK4 would be effective against a range of tumor types. We have screened a panel of tumor-derived cell lines from different origins including breast, prostate, ovarian and cervical cancer for SK4 sensitivity and we have found a range of differential sensitivities varying from 111.3 to >500 μM. We validated the iron chelation moiety as responsible for inducing cytotoxicity through control compounds; each lacking a key moiety. Following the screen, we conducted a series of assays to elucidate the mechanism of action behind SK4 cytotoxicity. SK4 was shown to induce apoptosis in triple negative breast cancer cell line MDA MB 231 but not ovarian cancer cell line SKOV3 suggesting SK4 may induce different modes of cell death in each cell line. As MDA MB 231 cells harbor a mutation in p53, we conclude SK4 is capable of inducing apoptosis in a p53-independent manner. SK4 upregulated NDRG1 expression in MDA MB 231 and SKOV3 cells. Interestingly, knockdown of NDRG1 antagonized SK4 in MDA MB 231 cells but not SKOV3 cells suggesting SK4's mechanism of action may be mediated through NDRG1 in MDA MB 231 cells. In conclusion, we have shown tagging iron chelators with an amino acid moiety to allow entry through the LAT1 transporter represents a double pronged approach to cancer therapy, targeting "iron addiction" and amino acid metabolism dysregulation.

Dataset Information

A novel, nontoxic iron chelator, super-polyphenol, effectively induces apoptosis in human cancer cell lines.

Publications

A novel, nontoxic iron chelator, super-polyphenol, effectively induces apoptosis in human cancer cell lines.

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