The overarching goal is to find platinum(II) complex drugs that show toxicity against cancer cells, while avoiding ototoxicity and hearing loss. This research will be conducted both in vitro, and in vivo in the zebrafish model. Current platinum-based drugs like cisplatin have diamine ligands and are highly ototoxic, i.e., produce sensory hair cell and hearing loss. Some novel platinum(II) complexes have triamine or heterocyclic ligands that exhibit unique DNA and protein binding properties that differ from that of complexes with diamine ligands. Dr. Kevin Williams (Biochemistry) at Western Kentucky University (WKU) has recently found differences in platinum(II) diamine and triamine complexes in their reactions with amino acid and nucleotide targets. These properties may result in reduced drug side effects such as ototoxicity. Dr. Michael Smith (Neurobiology) recently showed that ototoxicity could be examined in the zebrafish inner ear using two ototoxic chemicals- the aminoglycoside antibiotic gentamicin, and the platinum-based anti- cancer drug cisplatin. The proposed project is an interdisciplinary collaboration between these two laboratories at WKU. This proposal has two primary aims: 1) to determine whether novel platinum(II) complexes cause cytotoxicity to cancer cells, and 2) to determine whether the novel platinum(II) complexes are ototoxic (i.e., damage hair cells and cause hearing loss).
In aim 1, we will test six novel compounds in six different cancer cell lines for anticancer activity using cytotoxicity assays, inductively coupled plasma-emission spectroscopy (ICP-ES) to measure uptake of platinum into cancer cell nuclei, and DNA binding assays.
In aim 2, those compounds that are found to be cytotoxic to cancer cells in aim 1 will be tested for ototoxicity in a zebrafish inner ear model. Following microinjection with either a platinum-compound or buffer control, zebrafish hearing thresholds will be measured using auditory evoked potential (AEP) recording. Then the inner ears will be dissected and cell death and hair cell loss will be quantified in the sensory epithelia. The proposed study establishes a framework for understanding the effects of these novel platinum(II) complexes on cancer cells and hair cells, with the ultimate goal of providing the foundation for future investigations developing new chemotherapy drugs that avoid the side effect of hearing loss. This proposal accomplishes the AREA program objectives of: 1) supporting meritorious research; 2) exposing undergraduate and graduate students to research; and 3) strengthening the research environment in non- research intensive universities. Western Kentucky University aspires to be the best comprehensive public institution in Kentucky. This project supports this mission by enhancing the research environment and by providing undergraduate and graduate students with opportunities to be engaged in biomedical research, and supports both P.I.s' career goals of leading independently-funded research laboratories.
A half a million Americans a year experience hearing loss as a result of taking prescription drugs that are ototoxic, such as the anti-cancer chemotherapy compound cisplatin. The proposed project investigates novel platinum-based compounds for cancer cytotoxicity and ototoxicity using a zebrafish auditory hair cell model. The goal is to find novel platinum-based chemotherapy compounds that are less ototoxic than cisplatin, but are still effective at killing cancer cells.
| Monroe, Jerry D; Millay, Matthew H; Patty, Blaine G et al. (2018) The curcuminoid, EF-24, reduces cisplatin-mediated reactive oxygen species in zebrafish inner ear auditory and vestibular tissues. J Clin Neurosci 57:152-156 |
