Combination of heme oxygenase-1 inhibitors and temozolomide to improve the anticancer effect in glioblastoma

Heme oxygenase-1 (HO-1) is involved in the oncogenesis of glioblastoma (GBM). In this work, we investigated for the first time how the co-administration (combo) of the HO-1 inhibitors SI1/09 or LS6/42 with temozolomide (TMZ) or temozolomide acid (TMZ Ac) may influence the proliferation of U87MG GBM cell lines. Moreover, two novel TMZ/HO-1 inhibitors codrugs LS8/21 and LS8/24 were synthesised, characterised and tested. Results indicate that the combos TMZ or TMZ Ac with LS6/42, as well as the corresponding LS8/24, are more efficacious in reducing U87MG cell proliferation with respect to reference drugs, allowing a possible reduction of the TMZ dosage and related side effects in clinical practice. The chemical and enzymatic stability of the most potent codrug LS8/24 was evaluated. The observed high potency performed by both combos and LS8/24 in cells suggests that HO-1 inhibition may give additional contribution to the antiproliferative effect of TMZ.