Grade Level at Time of Presentation

Junior

Institution

Eastern Kentucky University

KY House District #

61

KY Senate District #

17

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.

Share

COinS
 

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.

 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.