Item Details

abstract

Epithelial Ovarian cancer (OvCa) is the leading cause of death from gynecologic malignancies in the United States, with approximately 75% of patients diagnosed at late stages. High-grade serous cancer (HGSC) is the most common subtype (∼70%) and accounts for the majority of deaths. Despite aggressive surgical debulking and chemotherapy, recurrence of a chemo-resistant disease occurs in almost 80% of patients and is attributed to the propensity of OvCa cells to disseminate in the peritoneal cavity. Thus, to effectively treat advanced OvCa and drive durable remissions and even cures, therapies must potently induce tumor-selective cell death and target their molecular, phenotypic and metabolic adaptations. One such therapeutics is dorsomorphin, or Compound C. The goal of this study is to evaluate and validate the therapeutic efficacy of compound C in OvCa. We found that CC not only inhibited OvCa growth and invasiveness, but also inhibited the reciprocal crosstalk between OvCa cells and macrophages, and mesothelial monolayers. Mechanistic studies indicated that compound C exerted its effects on OvCa cells through inhibition of PI3K-AKT-NFκB; whereas in macrophages and mesothelial cells, CC inhibited cancer-cell-induced canonical NFκB activation. Real-time monitoring of OvCa cellular bioenergetics revealed that compound C inhibited ATP production, mitochondrial respiration, and non-mitochondrial oxygen consumption. In addition, compound C significantly decreased tumor burden of SKOV3 xenografts in nude mice and increased their sensitivity to cisplatin-treatment. Together, our findings highlight Compound C as a potent multi-faceted therapeutic in OvCa.

subject

NFkB

Ovarian Cancer

PI3K Pathway

Tumor Microenvironment

contributor

GHONEUM, ALIA (author)

Said, Neveen (committee chair)

Kridel, Steven (committee member)

Furdui, Cristina (committee member)

Lo, Hui-Wen (committee member)

Watabe, Kounosuke (committee member)

date

2021-06-03T08:35:55Z (accessioned)

2023-06-02T08:30:11Z (available)

2021 (issued)

degree

Cancer Biology (discipline)

embargo

2023-06-02 (terms)

identifier

http://hdl.handle.net/10339/98786 (uri)

language

en (iso)

publisher

Wake Forest University

title

COMPOUND C INHIBITS OVARIAN CANCER PROGRESSION VIA PI3K/AKT/mTOR/NFκB PATHWAY

type

Dissertation