The opioid growth factor (OGF) and low dose naltrexone (LDN) suppress human ovarian cancer progression in mice
Highlights
► The OGF–OGFr axis is a determinant of the progression of human ovarian cancer. ► Exogenous OGF inhibited tumorigenesis in mice with intraperitoneal xenografts. ► Low-dose naltrexone suppressed the expression of human ovarian cancer in mice.
Introduction
Ovarian cancer is the leading cause of death from gynecological malignancies [1], and is the 5th leading cause of cancer mortality among women in the United States [2]. Approximately 75% of these women present in the advanced stages. Although clinical response to cytoreductive surgery and adjuvant chemotherapy is excellent [3], 65% of patients relapse within 2 years and thereafter only receive palliative care [1]. An understanding of the pathogenesis of ovarian cancer will be required in order to exploit biological pathways for treatment [1].
Dysregulation of cell proliferation is a fundamental component of the ovarian cancer phenotype [4]. The opioid growth factor (OGF) and its receptor (OGFr) have been reported to be a native biological regulator of cell replication in human ovarian cancer cells using a tissue culture model [5]. OGF, chemically termed [Met5]-enkephalin, is a constitutively active native opioid peptide that interacts with OGFr to upregulate cyclin-dependent kinase inhibitory (CKI) pathways and markedly delay the G1/S phase of the cell cycle [5], [6], [7], [8].
This study examined whether OGF depresses human ovarian cancer in vivo using an intraperitoneal xenograft model with parallels to the human situation. In addition, we have investigated another means to modulate the OGF–OGFr axis to alter the course of ovarian carcinogenesis using a low dose of the opioid antagonist naltrexone (LDN). LDN blocks endogenous opioids from opioid receptors for a short period of time (4–6 h), producing an upregulation of opioid systems [9], [10], [11]. For the remaining 18–20 h window each day, the elevated opioids and receptors interact to elicit a robust functional effect (e.g., growth inhibition) [10], [11]. We now show that both OGF and LDN have a marked effect on suppressing the progression of human ovarian cancer, suggesting that these agents may warrant clinical consideration as treatment modalities.
Section snippets
Cell culture
The human epithelial ovarian cancer cell line SKOV-3 [12], obtained from the American Type Culture Collection (Manassas, VA), was grown in a humidified atmosphere of 5% CO2/95% air at 37 °C in RPMI medium supplemented with 1.2% sodium bicarbonate, 10% fetal calf serum, 5000 units/ml penicillin, 5 μg/ml streptomycin, and 10 mg/ml neomycin.
Animals, xenografts, and treatments
Four week-old athymic nu/nu female mice, purchased from Charles River Laboratory (Wilmington, MA), were housed in pathogen-free isolator-ventilated cages in a
Body weight and gross observations
Body weights of mice administered OGF, LDN, or saline and inoculated with SKOV-3 cancer cells were comparable throughout the 40-day study (data not shown). Similarly, at the time of euthanasia, no changes in terminal spleen weight were noted in mice injected with tumor cells and receiving OGF, LDN, or saline, and no behavioral or ingestive (e.g., fluid consumption, feeding) abnormalities were noted in any group (data not shown).
OGF and LDN inhibit tumor burden in mice with intraperitoneal xenografts
Following 40 days of treatment, 100% of mice receiving saline or LDN
Discussion
The present study demonstrates for the first time that upregulation of the OGF–OGFr axis, by daily treatment with OGF or LDN, has a potent inhibitory effect on human ovarian tumorigenesis in a clinically relevant intraperitoneal xenograft model [13], [26]. Exposure to OGF or LDN significantly reduced the number of macroscopic tumor nodules in the peritoneal cavity of mice, as well as inhibited the cumulative weight of these neoplasms. The mechanism of inhibition by OGF and LDN treatments was
Conflict of interest statement
No author has a financial conflict of interest in regard to this work.
Acknowledgments
This work was supported in part by the Paul K. and Anna E. Shockey Family Foundation and Bonnie and Ken Shockey. We thank Moshe Rogosnitzky for initial discussions about the efficacy of OGF in modulating human ovarian cancer.
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2020, International ImmunopharmacologyCitation Excerpt :In support, the present study revealed increased tumor expression of OGFr. According to data from other studies, LDN upregulates and allow the activation of OGF/OGFr axis which enhances transcription of cyclin-inhibitory genes p16/p21 that hold cell cycle in G1/S phase and hence inhibit cellular proliferation [6,14,17,35]. The OGF-OGFr acts as a modulator of cell division in favor of biological situation such as in neoplasia it tends to reduce cell replication [6].
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