DNA Damage-Inducing Anticancer Therapies: From Global to Precision Damage

Abstract

DNA damage-inducing therapies are of tremendous value for cancer treatment and function by the direct or indirect formation of DNA lesions and subsequent inhibition of cellular proliferation. Of central importance in the cellular response to therapy-induced DNA damage is the DNA damage response (DDR), a protein network guiding both DNA damage repair and the induction of cancer-eradicating mechanisms such as apoptosis. A detailed understanding of DNA damage induction and the DDR has greatly improved our knowledge of the classical DNA damage-inducing therapies, radiotherapy and cytotoxic chemotherapy, and has paved the way for rational improvement of these treatments. Moreover, compounds targeting specific DDR proteins, selectively impairing DNA damage repair in cancer cells, form a promising novel therapy class that is now entering the clinic. In this review, we give an overview of the current state and ongoing developments, and discuss potential avenues for improvement for DNA damage-inducing therapies, with a central focus on the role of the DDR in therapy response, toxicity and resistance. Furthermore, we describe the relevance of using combination regimens containing DNA damage-inducing therapies and how they can be utilized to potentiate other anticancer strategies such as immunotherapy.

Natural Products as Inducers of Non-Canonical Cell Death: A Weapon against Cancer

“…In the same model, shikonin caused DNA damage [ 142 ] ( Table S4 ), as observed in several cancer cells in vitro [ 142 , 159 , 160 ] ( Table 2 ), thus configuring itself as a possible mutagen compound. This aspect is certainly to be taken into account in the evaluation of the toxicological profile of shikonin, even if it is worth noting that the antitumor activity of several anticancer drugs is based on DNA-damage induction [ 161 ]. In BALB/c nude mouse xenograft model of human osteosarcoma, shikonin reduced tumor growth, increased RIP1/3 expression, and reduced lung metastasis thus suggesting an antimetastatic activity for shikonin [ 138 ] ( Table S4 ).…”

“…However, attention must be paid since the role of necroptosis in cancer metastatization is controversial. Strilic et al reported that tumor cells-induced necroptosis of endothelial cells promotes cancer cells extravasation and metastatization through interaction with DR6 (death receptor 6) [ 162 ], hence showing that necroptosis could promote cancer cell metastatization [ 161 ]…”

Metformin Sensitizes Osteosarcoma Cells to Chemotherapy Through IGF-1R/miR-610/FEN1 Pathway

“…Cytotoxic chemotherapy causes severe DNA damage directly by induction of breaks or indirectly due to the formation of reactive oxygen species (ROS) and ultimately induce cell death 34,35 . In responses to DNA damage, cells recruit DNA repair factors to upregulate mutagenic repair pathways that to maintain survival 36 .…”

Gene Panel of Persister Cells as a Prognostic Indicator for Tumor Repopulation After Radiation

“…To maintain genomic integrity of normal cells, damaged DNA induces checkpoints (e.g. p53-p21)-controlled cell cycle arrest until that DNA repair is achieved or cell death is launched (25). Under this premise, malignant cells might sustain in G0 phase by activating other epigenetics or genetics-dependent quiescence programs (26).…”