Temozolomide, Procarbazine and Nitrosoureas in the Therapy of Malignant Gliomas: Update of Mechanisms, Drug Resistance and Therapeutic Implications

Abstract

The genotoxic methylating agents temozolomide (TMZ) and procarbazine and the chloroethylating nitrosourea lomustine (CCNU) are part of the standard repertoire in the therapy of malignant gliomas (CNS WHO grade 3 and 4). This review describes the mechanisms of their cytotoxicity and cytostatic activity through apoptosis, necroptosis, drug-induced senescence, and autophagy, interaction of critical damage with radiation-induced lesions, mechanisms of glioblastoma resistance to alkylating agents, including the alkyltransferase MGMT, mismatch repair, DNA double-strand break repair and DNA damage responses, as well as IDH-1 and PARP-1. Cyclin-dependent kinase inhibitors such as regorafenib, synthetic lethality using PARP inhibitors, and alternative therapies including tumor-treating fields (TTF) and CUSP9v3 are discussed in the context of alkylating drug therapy and overcoming glioblastoma chemoresistance. Recent studies have revealed that senescence is the main trait induced by TMZ in glioblastoma cells, exhibiting hereupon the senescence-associated secretory phenotype (SASP). Strategies to eradicate therapy-induced senescence by means of senolytics as well as attenuating SASP by senomorphics are receiving increasing attention, with therapeutic implications to be discussed.

The landscape of circRNAs in gliomas temozolomide resistance: Insights into molecular pathways

“…Many studies have shown that different mechanisms are involved in TMZ sensitivity or resistance. Various anticancer drugs have been used to increase the sensitivity of cancer cells to TMZ therapy py [ 57 , 58 ]. Oxyphyllanene B can cause TMZ sensitivity by overexpressing PACS2, which can interfere with and impair connection between the endoplasmic reticulum and mitochondria [ 50 ].…”

Activation of Epstein–Barr Virus’ Lytic Cycle in Nasopharyngeal Carcinoma Cells by NEO212, a Conjugate of Perillyl Alcohol and Temozolomide

“…TMZ is, in clinical use, part of the standard of care for the chemoradiation treatment of glioblastoma (GBM). Its primary cytotoxic mode of action is methylation of the O6-position of guanine, which results in DNA double-strand breaks and subsequent apoptosis [ 28 ]. However, this process does not work in cells that express the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), because MGMT is able to effectively remove the methyl group from the O6-position of guanine, thereby disposing of the toxic lesion and providing chemoresistance [ 29 ].…”

Overcoming Resistance to Temozolomide in Glioblastoma: A Scoping Review of Preclinical and Clinical Data

“…Gliom present a more alkaline environment compared to surrounding healthy brain cells, le ing to drug activation [1,3,4,7,8] almost exclusively in the tumor cells [1,7,8,13,14]. Mor ver, senescence induced by TMZ is another phenomenon that should also be mention TMZ senescent GB cells overexpress NF-kB and lead to inflammatory cytokines' prod tion, such as IL6 and IL8; thus, these cells seem not to be eliminated after TMZ and rad therapy and tend to be present even in recurrence of the tumor, with a not yet fully cla fied role [15]. Due to the highly heterogeneous and mutation-prone nature of GB, resistance to TMZ is developed and accounts for over 50% of GB patients that eventually fail to respond to the therapy [16].…”

“…Moreover, senescence induced by TMZ is another phenomenon that should also be mentioned. TMZ senescent GB cells overexpress NF-kB and lead to inflammatory cytokines’ production, such as IL6 and IL8; thus, these cells seem not to be eliminated after TMZ and radiotherapy and tend to be present even in recurrence of the tumor, with a not yet fully clarified role [ 15 ].…”