Grade Level at Time of Presentation
Junior
Major
Biomedical Sciences
Minor
Chemistry
Institution
Eastern Kentucky University
KY House District #
61
KY Senate District #
17
Faculty Advisor/ Mentor
Dr. Lindsay Calderon
Department
Biological Sciences
Abstract
In the United States one in eight women will be afflicted with breast cancer. It is estimated that in 2016 there will be approximately 246,600 new invasive breast cancer cases and 61,000 new non-invasive cases. Triple negative breast cancers account for 15% of all breast cancers and are significantly more aggressive than other subtypes. Treatment options for triple negative breast cancer are limited due to the cancers not expressing the estrogen, progestogen, or herceptin receptors making them unresponsive to hormonal therapy. Our recent work centers around developing a novel chemotherapeutic agent that will direct therapy selectively to triple negative (4T1) cancer cells while decreasing systemic distribution.
Others have reported an upregulation of the luteinizing hormone-releasing hormone (LHRH) receptor on 4T1 cells. We have designed and synthesized a Pt-Mal-LHRH compound that uses the LHRH peptide to selectively target and deliver Platinum intracellularly to the 4T1 cells. Platinum has been used in chemotherapy for approximately 20 years in the commonly used compounds cisplatin and carboplatin. Both cisplatin and carboplatin are effective chemotherapeutic agents, however, they are not cancer specific and elicit debilitating side effects including nephrotoxicity, myelotoxicity, and neurotoxicity.
To address, whether Pt-Mal-LHRH is more selective and efficacious than carboplatin we have designed in-vitro experiments to compare the chemotherapeutic agents. First, we verified that Pt-Mal-LHRH reduces 4T1 proliferation through an MTT assay. We found that Pt-Mal-LHRH significantly reduces 4T1 viability compared to carboplatin. Next, we found through flow cytometry that Pt-Mal-LHRH significantly increases 4T1 apoptosis compared to carboplatin. In addition, we found there is a 20 fold increase in cellular uptake of Pt-Mal-LHRH compared to carboplatin. Taken together we have found that Pt-Mal-LHRH significantly increases 4T1 cell death through increased cellular uptake. Our future directions will decipher the molecular mechanism of action including DNA binding rates and adduct formation.
Pt-Mal-LHRH Mediates Breast Cancer Cell Cytotoxicity Through Increased Apoptosis
In the United States one in eight women will be afflicted with breast cancer. It is estimated that in 2016 there will be approximately 246,600 new invasive breast cancer cases and 61,000 new non-invasive cases. Triple negative breast cancers account for 15% of all breast cancers and are significantly more aggressive than other subtypes. Treatment options for triple negative breast cancer are limited due to the cancers not expressing the estrogen, progestogen, or herceptin receptors making them unresponsive to hormonal therapy. Our recent work centers around developing a novel chemotherapeutic agent that will direct therapy selectively to triple negative (4T1) cancer cells while decreasing systemic distribution.
Others have reported an upregulation of the luteinizing hormone-releasing hormone (LHRH) receptor on 4T1 cells. We have designed and synthesized a Pt-Mal-LHRH compound that uses the LHRH peptide to selectively target and deliver Platinum intracellularly to the 4T1 cells. Platinum has been used in chemotherapy for approximately 20 years in the commonly used compounds cisplatin and carboplatin. Both cisplatin and carboplatin are effective chemotherapeutic agents, however, they are not cancer specific and elicit debilitating side effects including nephrotoxicity, myelotoxicity, and neurotoxicity.
To address, whether Pt-Mal-LHRH is more selective and efficacious than carboplatin we have designed in-vitro experiments to compare the chemotherapeutic agents. First, we verified that Pt-Mal-LHRH reduces 4T1 proliferation through an MTT assay. We found that Pt-Mal-LHRH significantly reduces 4T1 viability compared to carboplatin. Next, we found through flow cytometry that Pt-Mal-LHRH significantly increases 4T1 apoptosis compared to carboplatin. In addition, we found there is a 20 fold increase in cellular uptake of Pt-Mal-LHRH compared to carboplatin. Taken together we have found that Pt-Mal-LHRH significantly increases 4T1 cell death through increased cellular uptake. Our future directions will decipher the molecular mechanism of action including DNA binding rates and adduct formation.