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Salmonella typhimurium‐derived Virulence Protein Overcomes Multidrug Resistance in Tumors
Author(s) -
MercadoLubo Regino,
Hang Gang,
McCormick Beth A.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.178.2
Subject(s) - multiple drug resistance , in vivo , doxorubicin , cancer research , virulence , in vitro , cytotoxic t cell , cancer cell , drug resistance , cancer , intracellular , salmonella , microbiology and biotechnology , chemistry , biology , chemotherapy , bacteria , gene , biochemistry , genetics
We have recently developed a novel therapeutic platform for the treatment of cancers that over‐express the multidrug resistance transporter P‐glycoprotein (P‐gp), a major impediment for the success of conventional chemotherapy. This technology is based on our discovery that a Salmonella typhimurium ‐derived virulence protein, SipA, not only functionally down‐regulates P‐gp, but also potentiates the cytotoxic effect of chemotherapeutics such as doxorubicin and vinblastine in vitro by significantly increasing the intracellular accumulation of the drugs. To safely deliver SipA in our in vivo models of cancer, we engineered a carboxyl modified 15nm gold nanoparticle (AUNP) packed with a SipA corona to create a SipA‐AuNP biomimetic. We found that SipA‐AuNPs, when used in combination with doxorubicin, promote tumor regression in a subcutaneous model of murine colon cancer, as well as a patient‐derived xenograft mouse model of breast cancer. We are currently working to identify the specific SipA domain responsible for the down‐regulation of P‐gp. Thus far, SipA has been truncated into two fragments: a SipAb C‐terminal fragment 426–684 (259 AA), which binds actin, and a SipAa fragment 2–425 (424 AA), known for its ability to induce pro‐inflammatory responses. When used in in vitro models of colon cancer, the SipAa fragment exhibits a conserved ability to down‐regulate P‐pg (70% reduction compared to the negative control), whereas the SipAb fragment fails to reduce P‐gp. Concomitantly, we are evaluating the ability of SipA to increase the efficacy of other known P‐gp substrates, such as etoposide, daunorubicin and paclitaxel, since this effect is specific to drugs efluxed by P‐gp. Using a cell proliferation assay, in which human colon carcinoma cells are cultured in media containing etoposide with or without purified‐SipA, we have found that those with SipA exhibit a profound reduction in the IC 50 (50.20±0.30 to 8.05±1.15 μM). Given that we observe improved cytotoxicity of drugs effluxed by P‐gp, we are now implementing novel patient‐derived xenograft mouse models of cancers that use P‐gp substrates (i.e. doxorubicin and etoposide) as the first line of treatment, such as of B‐cell lymphomas and ovarian cancer. We believe that SipA could present a significant advancement as an adjuvant therapy when compared to previous P‐gp reversal agents. Furthermore, SipA can potentially facilitate repurposing old cancer drugs and help reduce the amount the chemotherapeutics needed for effective treatment, thereby reducing the side effects associated with chemotherapy. Support or Funding Information National Institutes of Health Grants DK56754 and DK33506 awarded to Beth A. McCormickThe Worcester Foundation, and by a UMCCTS Pilot Project Program award (CTSA Grant # UL1TR000161) awarded to Beth A. McCormick Massachusetts Medical School start‐up fund and National Institutes of Health grant R01MH103133