Effect of ethinylestradiol and levonorgestrel on nucleoside reverse transcriptase inhibitor-induced apoptosis in human cervical epithelial cancer cells

Abstract

Preliminary findings suggest an increase in cervical cancer among sub-Sahara African women on highly active antiretroviral treatment (HAART). There has been a sharp rise in serious non-AIDS events among HAART recipients. This study explored the effect of co-administering combined contraceptive hormones with antiretroviral drugs on promoting human cervical epithelial cancer cell proliferation, DNA mutation and cell transformation. Combinations of abacavir (ABC), zidovudine (ZDV), lamivudine (3TC), stavudine (d4T) and nevirapine (NVP) were co-administered with either ethinylestradiol or levonorgestrel.

The combinations ZDV+3TC, ABC+ZDV+3TC, ZDV+3TC+NVP and d4T+3TC+NVP induced a time-dependent antiproliferative effect on HeLa cells. Co-treatment with levonorgestrel demonstrated antiproliferative effects on combination antiretroviral drug-treated cells while co-administering 0.5μg/ml ethinylestradiol increases HeLa cell proliferation (P≤ 0.5). Single drugs (ABC, ZDV, 3TC, d4T and NVP) showed a time-dependent DNA double strand breakage in both HeLa and Chinese hamster ovary cells. Both levonorgestrel and ethinylestradiol drastically increased apoptosis in ABC+3TC-, ZDV+3TC-, ABC+ZDV+3TC- and d4T+3TC+NVP-treated cells. Highly active antiretroviral treatment transformed pre-monocyte lymphoma (U937) cells to adherent cells with macrophage-like morphology and increased superoxide production.

Increased HeLa cell death by apoptosis following co-administration of triple combination antiretroviral drugs with levonorgestrel suggests a protective effect against human cervical cancer cell proliferation among HAART users. Despite the drastic induction of apoptosis by 0.5μg/ml ethinylestradiol, ABC+3T-, ZDV+3TC-, ABC+ZDV+3TC- and ZDV+3TC+NVP-treated cells did not significantly differ from the untreated cells in their proliferation assayed by MTT (P≤0.05), thus suggesting a proliferative effect on the human cervical epithelial cancer cells. Transformation to macrophage-like morphology and increased superoxide anion production in U937 cells suggest precipitation of serious non-AIDs events among HAART users.

The antiproliferative effect of HAART on cervical cancer cells suggests a protective role against cell proliferation. The antiproliferative effect of levonorgestrel suggests its potential as a progestogen-only contraceptive alternative for women on HAART treatment. The present results also suggest the downside effect of HAART through precipitation of serious non-AIDS events. Further in vivo clinical studies maybe of interest.

Date of Award	2 Oct 2019
Original language	English
Awarding Institution	University of Bath
Supervisor	Michael Threadgill (Supervisor), Giordano Pula (Supervisor) & Winston Morgan (Supervisor)