Abstract:
Adult T-cell leukemia/lymphoma (ATL) is a severe and rare T-cell malignancy caused by an aggressive human T-cell leukemia virus type-1 (HTLV-1) infection. ATL has a dismal prognosis and is highly resistant to chemotherapy, hence there is an urgent need for alternative treatments. The viral oncoprotein Tax plays a major role in ATL tumorigenesis, making it a major therapeutic target. Retinoids or vitamin A derivatives, such as all-trans retinoic acid (ATRA), are used in the treatment of certain leukemias. Synthetic retinoids were developed to increase specificity and decrease toxicity, as compared to natural retinoids. The adamantyl ST1926 is a synthetic retinoid-related molecule that has demonstrated promising activities in ATL in vitro and in vivo models, however the drug showed poor pharmacokinetics in clinical trials. We have recently shown that ST1926 targets and inhibits DNA polymerase α (POLA1), the catalytic subunit of the DNA polymerase α which is the initiating enzyme in DNA synthesis. An ST1926 analogue (ST-A) was recently developed to improve the pharmacological profile of ST1926. ST-A exerted potent anti-proliferative and antitumor effects in a wide range of cancer cells, hence overcoming ST1926 resistance. Furthermore, STA versus ST1926, displayed an enhanced pharmacological profile. In the current study, we aimed at investigating the antitumor effect of ST-A using ATL and T lymphoma in vitro models.
We selected six T malignant cell lines, three of which are HTLV-1 positive cells and three HTLV-1 negative cells. Normal lymphocytes from six normal donors were also tested as a control. We showed that sub-micromolar concentrations of ST-A inhibited irreversibly the proliferation of all tested malignant T cells. Interestingly, ST-A inhibited the viability of ATL cells, at sub-micromolar concentrations, while sparing normal cells, even at ten-fold higher concentrations. Moreover, ST-A induced apoptosis as evidenced by PARP cleavage and by the accumulation of treated cells in the sub-G1 region of the cell cycle in some cells. ST-A also induced cell cycle arrest evidenced by the accumulation of treated cells in the G0/G1 phase. Furthermore, ST-A treatment decreased POLA1 protein levels and induced early γH2AX expression in the tested malignant cell lines, and reduced Tax protein expression in ATL cells.
Our study highlights a potential therapeutic role of ST-A in ATL and peripheral T lymphomas and warrant its in vivo testing in preclinical animal models.