Laura Cabeza

BACKGROUND: The use of temozolomide (TMZ) has improved the prognosis for glioblastoma multiforme patients. However, TMZ resistance may be one of the main reasons why treatment fails. Although this resistance has frequently been linked to the expression of O6-methylguanine-DNA methyltransferase (MGMT) it seems that this enzyme is not the only molecular mechanism that may account for the appearance of drug resistance in glioblastoma multiforme patients as the mismatch repair (MMR) complex, P-glycoprotein, and/or the presence of cancer stem cells may also be implicated. METHODS: Four nervous system tumor cell lines were used to analyze the modulation of MGMT expression and MGMT promoter methylation by TMZ treatment. Furthermore, 5-aza-2'-deoxycytidine was used to demethylate the MGMT promoter and O(6)-benzylguanine to block GMT activity. In addition, MMR complex and P-glycoprotein expression were studied before and after TMZ exposure and correlated with MGMT expression. Finally, the effect of TMZ exposure on CD133 expression was analyzed. RESULTS: Our results showed two clearly differentiated groups of tumor cells characterized by low (A172 and LN229) and high (SF268 and SK-N-SH) basal MGMT expression. Interestingly, cell lines with no MGMT expression and low TMZ IC50 showed a high MMR complex expression, whereas cell lines with high MGMT expression and high TMZ IC50 did not express the MMR complex. In addition, modulation of MGMT expression in A172 and LN229 cell lines was accompanied by a significant increase in the TMZ IC50, whereas no differences were observed in SF268 and SK-N-SH cell lines. In contrast, P-glycoprotein and CD133 was found to be unrelated to TMZ resistance in these cell lines. CONCLUSIONS: These results may be relevant in understanding the phenomenon of TMZ resistance, especially in glioblastoma multiforme patients laking MGMT expression, and may also aid in the design of new therapeutic strategies to improve the efficacy of TMZ in glioblastoma multiforme patients.

Polymeric nanofibers (NFs) have been extensively reported as a biocompatible scaffold to be specifically applied in several researching fields, including biomedical applications. The principal researching lines cover the encapsulation of antitumor drugs for controlled drug delivery applications, scaffolds structures for tissue engineering and regenerative medicine, as well as magnetic or plasmonic hyperthermia to be applied in the reduction of cancer tumors. This makes NFs useful as therapeutic implantable patches or mats to be implemented in numerous biomedical researching fields. In this context, several biocompatible polymers with excellent biocompatibility and biodegradability including poly lactic-co-glycolic acid (PLGA), poly butylcyanoacrylate (PBCA), poly ethylenglycol (PEG), poly (ε-caprolactone) (PCL) or poly lactic acid (PLA) have been widely used for the synthesis of NFs using the electrospun technique. Indeed, other types of polymers with stimuli-responsive capabilities has have recently reported for the fabrication of polymeric NFs scaffolds with relevant biomedical applications. Importantly, colloidal nanoparticles used as nanocarriers and non-biodegradable structures have been also incorporated by electrospinning into polymeric NFs for drug delivery applications and cancer treatments. In this review, we focus on the incorporation of drugs into polymeric NFs for drug delivery and cancer treatment applications. However, the principal novelty compared with previously reported publications is that we also focus on recent investigations concerning new strategies that increase drug delivery and cancer treatments efficiencies, such as the incorporation of colloidal nanoparticles into polymeric NFs, the possibility to fabricate NFs with the capability to respond to external environments, and finally, the synthesis of hybrid polymeric NFs containing carbon nanotubes, magnetic and gold nanoparticles, with magnetic and plasmonic hyperthermia applicability.

Temozolomide (TMZ), an oral alkylating prodrug which delivers a methyl group to purine bases of DNA (O6-guanine; N7-guanine and N3-adenine), is frequently used together with radiotherapy as part of the first-line treatment of high-grade gliomas. The main advantages are its high oral bioavailability (almost 100% although the concentration found in the cerebrospinal fluid was approximately 20% of the plasma concentration of TMZ), its lipophilic properties, and small size that confer the ability to cross the blood-brain barrier. Furthermore, this agent has demonstrated activity not only in brain tumors but also in a variety of solid tumors. However, conventional therapy using surgery, radiation, and TMZ in glioblastoma results in a median patient survival of 14.6 months. Treatment failure has been associated with tumor drug resistance. This phenomenon has been linked to the expression of O6-methylguanine-DNA methyltransferase, but the mismatch repair system and the presence of cancer stem-like cells in tumors have also been related to TMZ resistance. The understanding of these mechanisms is essential for the development of new therapeutic strategies in the clinical use of TMZ, including the use of nanomaterial delivery systems and the association with other chemotherapy agents. The aim of this review is to summarize the resistance mechanisms of TMZ and the current advances to improve its clinical use.

Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates among all cancer types. Its delayed diagnosis precludes curative resection, thus most of the current therapies against PDAC are based on chemo- and radiotherapy. Unfortunately, these strategies are insufficient to improve its poor prognosis. Despite the advances made in chemotherapy (e.g. nab-paclitaxel and gemcitabine), many patients with PDAC are unable to benefit from them due to the rapid development of drug resistance. Currently, more than 165 genes have been found to be implicated in drug resistance of pancreatic tumors, including different integrins, mucins, NF-κB, RAS and CXCR4. Moreover, drug resistance in PDAC is thought to be mediated by the modulation of miRNAs (e.g. miRNA-21, miRNA-145 and miRNA-155), which regulate genes that participate in cell proliferation, invasion and metastasis. Finally, cancer stem cells are intimately related to drug resistance in PDAC due to their ability to overexpress ABC genes -involved in drug transport-, and enzymes such as aldehyde dehydrogenases -implicated in cellular drug metabolism- and poly (ADP-ribose) polymerases -involved in drug-induced DNA damage repair. Understanding the mechanisms involved in drug resistance will contribute to the development of efficient therapeutic strategies and to improve the prognosis of patients with PDAC.