Nemec, Matthew James (2016-08). Polyphenolics from Mango (Mangifera Indica L.) Suppress Breast Cancer Ductal Carcinoma In Situ Proliferation Both In Vitro And In Vivo: Potential Role of the IGFR-1-AKT-AMPK-mTOR-Signaling Axis. Doctoral Dissertation. Thesis uri icon

abstract

  • More than 25% of all newly diagnosed breast cancer cases are ductal carcinoma in situ (DCIS), the most commonly diagnosed form of non-invasive breast cancer. This incidence coupled with the detrimental side effects associate with traditional cancer treatment makes it critical to investigate the efficacy of alternative treatment regimens that are not as toxic to non-cancer cells. The tumor-cytotoxic activities of secondary plant compounds including polyphenolics from mango (Mangifera indica L.) have previously been reported; however, the underlying mechanism, especially with DCIS breast cancer, has not been elucidated. In both an in vitro and an in vivo xenograft assessment of mango extract and pyrogallol (PG), a tannin-metabolite formed by bacteria in the gastrointestinal tract, had anti-proliferative activities in the DCIS cell line MCF10DCIS.com. Reduced proliferation in vitro was attributed to a down-regulation of multiple constituents along the AKT/mTOR signaling axis. Within a low concentration of 10 mg/L both treatments significantly decreased total protein for mTOR and p-AKT and p-P70S6. Neither treatment had significant interaction with 5-fluoro-uracil. In a xenograft model, the mango extract (0.8mg/day) and PG (0.2mg/day) significantly reduced tumor volumes by 50% over a 4 week exposure window where similar downregulation of the AKT/mTOR signaling axis was observed as in vitro, however, AMPK and p-AMPK at Thr172 were also upregulated. Sestrin, Becklin, and p-ULK were all significantly elevated in tumor tissue by treatments. Both treatments were shown to cause elevated ROS production, which might have initiated the activation of AMPK. In silico modeling demonstrated PG ability to directly bind with the allosteric site of AMPK? resulting in its activation. PG treatment following siRNA knockdown to AMPK resulted in the rescue of total and p-AMPK levels in vitro. This indicates that PG is not only involved in the activation of AMPK but also in the upregulation of its constituent expression, possibly by the downregulation of HDAC1, a suppressor of AMPK expression. An assessment of mouse plasma indicated that PG is rapidly metabolized into pyrogallol sulfate, likely by intestinal and hepatic sulfotransferases. Findings indicate that tannin-containing foods or PG may delay the development of DCIS breast cancer.
  • More than 25% of all newly diagnosed breast cancer cases are ductal carcinoma in situ (DCIS), the most commonly diagnosed form of non-invasive breast cancer. This incidence coupled with the detrimental side effects associate with traditional cancer treatment makes it critical to investigate the efficacy of alternative treatment regimens that are not as toxic to non-cancer cells. The tumor-cytotoxic activities of secondary plant compounds including polyphenolics from mango (Mangifera indica L.) have previously been reported; however, the underlying mechanism, especially with DCIS breast cancer, has not been elucidated.

    In both an in vitro and an in vivo xenograft assessment of mango extract and pyrogallol (PG), a tannin-metabolite formed by bacteria in the gastrointestinal tract, had anti-proliferative activities in the DCIS cell line MCF10DCIS.com. Reduced proliferation in vitro was attributed to a down-regulation of multiple constituents along the AKT/mTOR signaling axis. Within a low concentration of 10 mg/L both treatments significantly decreased total protein for mTOR and p-AKT and p-P70S6. Neither treatment had significant interaction with 5-fluoro-uracil.

    In a xenograft model, the mango extract (0.8mg/day) and PG (0.2mg/day) significantly reduced tumor volumes by 50% over a 4 week exposure window where similar downregulation of the AKT/mTOR signaling axis was observed as in vitro, however, AMPK and p-AMPK at Thr172 were also upregulated. Sestrin, Becklin, and p-ULK were all significantly elevated in tumor tissue by treatments. Both treatments were shown to cause elevated ROS production, which might have initiated the activation of AMPK. In silico modeling demonstrated PG ability to directly bind with the allosteric site of AMPK? resulting in its activation. PG treatment following siRNA knockdown to AMPK resulted in the rescue of total and p-AMPK levels in vitro. This indicates that PG is not only involved in the activation of AMPK but also in the upregulation of its constituent expression, possibly by the downregulation of HDAC1, a suppressor of AMPK expression. An assessment of mouse plasma indicated that PG is rapidly metabolized into pyrogallol sulfate, likely by intestinal and hepatic sulfotransferases. Findings indicate that tannin-containing foods or PG may delay the development of DCIS breast cancer.

publication date

  • August 2016