In search of effective therapies to overcome resistance to Temozolomide in brain tumours

Abstract

Glioblastoma multiforme is the most common and lethal brain tumour-type. The current standard of care includes Temozolomide (TMZ) chemotherapy. However, inherent and acquired resistance to TMZ thwart successful treatment.The direct repair protein methylguanine DNA methyltransferase (MGMT) removes the cytotoxic O6 -methylguanine (O 6-MeG) lesion delivered by TMZ and so its expression by tumours confers TMZ-resistance. DNA mismatch repair (MMR) is essential to process O 6-MeG adducts and MMR-deficiency leads to tolerance of lesions, resistance to TMZ and further DNA mutations. In this article, two strategies to overcome TMZ resistance are discussed: (1) synthesis of imidazotetrazine analogues -designed to retain activity in the presence of MGMT or loss of MMR; (2) preparation of imidazotetrazine-nanoparticles to deliver TMZ preferably to the brain and tumour site. Our promising results encourage belief in a future where better prognoses exist for patients diagnosed with this devastating disease.

Combinatory Treatment with miR-7-5p and Drug-Loaded Cubosomes Effectively Impairs Cancer Cells

“…In contrast, there was a weak effect on the viability of GB-derived cells when miR-7-5p or TMZ were added independently. As TMZ, an alkaline pro-drug belonging to the class of imidazotetrazinones, is the first choice in the treatment of GB [ 20 , 30 ], we also considered whether the effect of miR-7-5p was limited only to TMZ, or can also be observed when other drug classes are administered. The potential effect of the co-treatment of GB-derived cells with miRNA and alternative drugs was examined using carmustine (BCNU), which is a substitute chemotherapeutic agent used in the treatment of GB [ 30 ], and DOX, a standard and commonly used drug in general chemotherapy [ 31 , 32 ].…”

“…It was assumed that supplementing miRNAs with a chemotherapeutic agent may effectively reverse tumor chemoresistance, and at the same time, sustained drug delivery would efficiently kill cancer cells. The majority of studies focused on GB-derived model cell lines, since GB is the most frequent, aggressive and drug-resistant primary brain tumor found in adults [ 20 , 21 ]. GB is classified as a grade IV cancer, and most new cases are recorded among people aged 50–64 years old, as the risk of developing brain tumors increases with age.…”

Nitric oxide-elicited resistance to anti-glioblastoma photodynamic therapy

“…To date, however, none of these trials have dealt with cancer in general or brain cancer in particular, and none have employed anti-tumor PDT. Temozolimide (TMZ) has become one of the most widely used chemotherapeutics for glioblastoma; however, inherent or acquired resistance to this drug has limited its effectiveness [5,6] . Various approaches have been used in attempt to overcome this obstacle, but, thus far, it appears that the possibility of iNOS/NO-based resistance to TMZ has not been considered.…”

“…Malignant gliomas such as glioblastoma multiforme (GBM) are among the most aggressive and persistent of all known human tumors [ 1 – 3 ] . These malignancies are known to be highly resistant to most conventional interventions, including ionizing radiation and chemotherapy with drugs such as cisplatin and more recently introduced temozolomide [ 4 – 6 ] . Drug resistance can either be inherent or acquired during treatment [ 5 , 6 ] .…”

“…These malignancies are known to be highly resistant to most conventional interventions, including ionizing radiation and chemotherapy with drugs such as cisplatin and more recently introduced temozolomide [ 4 – 6 ] . Drug resistance can either be inherent or acquired during treatment [ 5 , 6 ] . One of the advantages of non-ionizing photodynamic therapy (PDT) is that it can often overcome or circumvent chemo- and radiotherapeutic resistance, yet various forms of treatment-induced resistance also exist for PDT [ 7 – 9 ] .…”