Date of Award
Spring 5-2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Pharmaceutical Sciences
First Advisor
Sun Yang
Second Advisor
Anand Ganesan
Third Advisor
Jennifer Totonchy
Fourth Advisor
Miao Zhang
Abstract
Human cutaneous melanoma is the most aggressive form of skin cancer and the incidence rates have continued to increase over the years. Neuronal nitric oxide synthase (nNOS) produces nitric oxide (NO) has been found to be overexpressed in human melanoma and the expression of nNOS is induced by interferon-gamma (IFN-γ). In our studies, nNOS has been implicated in IFN-γ-stimulated melanoma progression and the inhibition of nNOS using novel inhibitors effectively inhibited IFN-γ-stimulated tumor growth in a xenograft mouse model. Programmed death-ligand 1 (PD-L1) is overexpressed in melanoma and plays an important role in suppressing the immune system 12-14. Our in vitro and in vivo studies show that nNOS inhibitors exhibit potent cytotoxicity to melanoma cells and have immune modulating potential through the inhibition of PD-L1. In an immunocompetent allograft mouse model, daily intraperitoneal injections of nNOS inhibitors (HH044 or MAC-3-190) exhibited significant anti-melanoma activity and inhibited tumor growth, which was enhanced when combined with immune checkpoint inhibitors. The co-treatment with HH044 and anti-PD-1 immunotherapy significantly prolonged mouse survival compared to the control group. Of note, no significant distress, or alterations in appearance or behavior were noted during the study.
Fluorescence-tagged confirmed that HH044 distributed to the tumor xenografts as detected by in vivo and ex vivo imaging. Consistently, further analysis demonstrated that nNOS inhibitor MAC-3-190 reached efficacious intratumor levels 30 minutes after a single i.p. injection and 24 hours after prolonged treatment. The utilization of targeting ligands was trialed to avoid possible adverse events and to improve the delivery of compounds to human melanoma cells. By screening a peptide library, we identified a peptide, KK-11, that binds specifically to and is internalized by melanoma cells. Our in vivo studies showed that a physical mixture of targeting peptide KK-11 with MAC-3-190 enhanced its anti-tumor activity in a human melanoma xenograft mouse model.
Targeting peptides can allow for the utilization of a smaller quantity of the active drug and the sparing of normal tissues and organs from toxicity. Our strategy of developing specific nNOS targeted therapeutic interventions and melanoma targeted delivery to block disease progression will have both high impact and importance.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Recommended Citation
Tong, S. Targeting Neuronal Nitric Oxide Synthase (nNOS) for Melanoma Treatment. [dissertation]. Irvine, CA: Chapman University; Year. https://doi.org/10.36837/chapman.000360
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