Targeting Gliomas: Can a New Alkylating Hybrid Compound Make a Difference?
Glioblastoma (GBM) is the most common and aggressive type of brain tumor in adults. The triazene Temozolomide (TMZ), an alkylating drug, is the classical chemotherapeutic agent for gliomas, but has been disappointing against the highly invasive and resistant nature of GBM. Hybrid compounds may open new horizons within this challenge. The multicomponent therapeutic strategy here used resides on a combination of two repurposing drugs acting by different but potentially synergistic mechanisms, improved efficacy, and lower resistance effects. We synthesized a new hybrid compound (HYBCOM) by covalently binding a TMZ analogue to valproic acid, a histone deacetylase inhibitor drug that was shown to sensitize TMZ-resistant glioma cells. Advantages of this new molecule as compared to TMZ, in terms of chemotherapeutic efficacy, were investigated. Our results evidenced that HYBCOM more efficiently decreased the viability and proliferation of the GL261 glioma cells, while showing to better target the tumor cells than the functionally normal astrocytes. Increased cytotoxicity by HYBCOM may be a consequence of the improved autophagic process observed. Additionally, HYBCOM changed the morphology of GL261 cells into a nonpolar, more rounded shape, impairing cell migration ability. Most interesting, and in opposite to TMZ, cells exposed to HYBCOM did not enhance the expression of drug resistance proteins, a major issue in the treatment of GBM. Overall, our studies indicate that HYBCOM has promising chemotherapeutic benefits over the classical TMZ, and future studies should assess if the treatment translates into efficacy in glioblastoma experimental models and reveal clinical benefits in GBM patients.
Research Institute for Medicines (iMed.ULisboa), ‡Department of Biochemistry and Human Biology, §Department of Pharmaceutical Chemistry and Therapeutics, and ∥Department of Toxicological and Bromatological Sciences, Faculty of Pharmacy, Universidade de Lisboa , Avenida Professor Gama Pinto, 1649-003 Lisbon, Portugal.
Rui
R
Pinheiro
Research Institute for Medicines (iMed.ULisboa), ‡Department of Biochemistry and Human Biology, §Department of Pharmaceutical Chemistry and Therapeutics, and ∥Department of Toxicological and Bromatological Sciences, Faculty of Pharmacy, Universidade de Lisboa , Avenida Professor Gama Pinto, 1649-003 Lisbon, Portugal.
Cláudia
C
Braga
Research Institute for Medicines (iMed.ULisboa), ‡Department of Biochemistry and Human Biology, §Department of Pharmaceutical Chemistry and Therapeutics, and ∥Department of Toxicological and Bromatological Sciences, Faculty of Pharmacy, Universidade de Lisboa , Avenida Professor Gama Pinto, 1649-003 Lisbon, Portugal.
Gisela
G
Santos
Research Institute for Medicines (iMed.ULisboa), ‡Department of Biochemistry and Human Biology, §Department of Pharmaceutical Chemistry and Therapeutics, and ∥Department of Toxicological and Bromatological Sciences, Faculty of Pharmacy, Universidade de Lisboa , Avenida Professor Gama Pinto, 1649-003 Lisbon, Portugal.
Maria R
MR
Bronze
Research Institute for Medicines (iMed.ULisboa), ‡Department of Biochemistry and Human Biology, §Department of Pharmaceutical Chemistry and Therapeutics, and ∥Department of Toxicological and Bromatological Sciences, Faculty of Pharmacy, Universidade de Lisboa , Avenida Professor Gama Pinto, 1649-003 Lisbon, Portugal.
Maria J
MJ
Perry
Research Institute for Medicines (iMed.ULisboa), ‡Department of Biochemistry and Human Biology, §Department of Pharmaceutical Chemistry and Therapeutics, and ∥Department of Toxicological and Bromatological Sciences, Faculty of Pharmacy, Universidade de Lisboa , Avenida Professor Gama Pinto, 1649-003 Lisbon, Portugal.
Rui
R
Moreira
Research Institute for Medicines (iMed.ULisboa), ‡Department of Biochemistry and Human Biology, §Department of Pharmaceutical Chemistry and Therapeutics, and ∥Department of Toxicological and Bromatological Sciences, Faculty of Pharmacy, Universidade de Lisboa , Avenida Professor Gama Pinto, 1649-003 Lisbon, Portugal.
Dora
D
Brites
Research Institute for Medicines (iMed.ULisboa), ‡Department of Biochemistry and Human Biology, §Department of Pharmaceutical Chemistry and Therapeutics, and ∥Department of Toxicological and Bromatological Sciences, Faculty of Pharmacy, Universidade de Lisboa , Avenida Professor Gama Pinto, 1649-003 Lisbon, Portugal.
Ana S
AS
Falcão
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000077204:Temozolomide
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide
Autophagy; glioblastoma; glioma cell migration; hybrid compound; multidrug resistance proteins; temozolomide