AUTHOR=Gamal-Eldeen Amira M. , Agwa Hussein S. , Zahran Magdy A.-H. , Raafat Bassem M. , El-Daly Sherien M. , Banjer Hamsa J. , Almehmadi Mazen M. , Alharthi Afaf , Hawsawi Nahed M. , Althobaiti Fayez , Abo-Zeid Mona A. M. 

TITLE=Phthalimide Analogs Enhance Genotoxicity of Cyclophosphamide and Inhibit Its Associated Hypoxia

JOURNAL=Frontiers in Chemistry

VOLUME=Volume 10 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2022.890675

DOI=10.3389/fchem.2022.890675

ISSN=2296-2646

ABSTRACT=Cyclophosphamide (CP) is a mutagen that is used as a cancer chemotherapy, due to its genotoxicity ‎and as immunosuppressive agent. Thalidomide (TH) is another cancer chemotherapeutic drug. In ‎this study, the cytogenotoxicity and hypoxia modulatory activity of  two phthalimide analogs of TH ‎have been evaluated with/without CP. Both analogs have increased CP-stimulated chromosomal ‎aberrations than that induced by TH, including gaps, breaks/fragments, deletions, multiple ‎aberrations and tetraploidy. The analogs have elevated the cytotoxic effect of CP by inhibiting the ‎mitotic activity, where analog 2 showed higher mitosis inhibition. CP has induced binucleated and ‎polynucleated bone marrow cells (BMCs) while micronuclei (MN) are absent. TH and analogs have ‎elevated the CP-stimulated binucleated BMCs, while only analogs have increased the CP-induced ‎polynucleated BMCs and inhibited the mononucleated BMCs. MN-BMCs were showed together with ‎mononucleated, binucleated and polynucleated cells in CP group. Both analogs have elevated ‎mononucleated and polynucleated MN-BMCs, whereas in CP presence, TH and analogs have ‎enhanced mononucleated and binucleated MN-BMCs. The analogs significantly induce DNA ‎fragmentation in comet assay, where analog 1 is the strongest inducer. The treatment of mice with ‎CP has resulted in a high hypoxia status as indicated by high pimonidazole adducts and high HIF-1α ‎and HIF-2α concentrations in lymphocytes. Analogs/CP-treated mice showed low pimonidazole ‎adducts. Both analogs have inhibited HIF-1α concentration but not HIF-2α. Taken together, the study ‎findings suggest that both analogs have a higher potential to induce CP-genotoxicity than TH and ‎that both analogs inhibit CP-hypoxia via HIF-1α-dependent mechanism, where analog 1 is more ‎potent anti-hypoxic agent than analog 2. Analog 1 is suggested as adjacent CP-complementary ‎agent to induce CP-genotoxicity and to inhibit CP-associated hypoxia.‎