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During fractionated radiotherapy, DNA damage repair intensifies in tumor cells, culminating in cancer radioresistance and subsequent radiotherapy failure. Despite the recent development of nanoradiosensitizers targeting specific DNA damage repair pathways, the persistence of repair mechanisms involving multiple pathways remains inevitable. To address this challenge, a nucleophilicity-engineered DNA ligation blockade nanoradiosensitizer (DLBN) comprising Au/CeO2 heteronanostructure modified with trans-acting activator of transcription peptides is reported, which targets and inhibits the DNA ligation inside cancer cell nuclei via heterointerface-mediated dephosphorylation of DNA, a crucial step in overcoming cancer radioresistance. First, the Schottky-type heteronanostructure of cancer cell nucleus-targeting DLBN effectively intensifies radiation-induced DNA damage via catalase-mimetic activity and radiation-triggered catalytic reactions. Notably, by leveraging Au/CeO2 heterointerface, DLBN spontaneously dissociates H2O to hydroxide, a nucleophile with higher nucleophilicity, thereby exhibiting remarkable dephosphorylation capability at DNA nicks through facilitated nucleophilic attack. This enables the blockade of DNA ligation, a pivotal step in all DNA damage repair pathways, effectively interrupting the repair process. Consequently, DLBN resensitizes radioresistant cells by overcoming therapy-induced radioresistance, leading to a substantial accumulation of unrepaired DNA damage. These findings offer insight into the dephosphorylation of DNA within nuclei, and underscore the potential of heteronanostructure-based nanoradiosensitizer to block DNA ligation against therapy-induced radioresistance.

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Mitochondria are very important intracellular organelles because they have various functions. They produce ATP, are involved in cell signaling and cell death, and are a major source of reactive oxygen species (ROS). Mitochondria have their own DNA (mtDNA) and mutation of mtDNA or change the mtDNA copy numbers leads to disease, cancer chemo/radioresistance and aging including longevity. In this review, we discuss the mtDNA mutation, mitochondrial disease, longevity, and importance of mitochondrial dysfunction in cancer first. In the later part, we particularly focus on the role in cancer resistance and the mitochondrial condition such as mtDNA copy number, mitochondrial membrane potential, ROS levels, and ATP production. We suggest a therapeutic strategy employing mitochondrial transplantation (mtTP) for treatment-resistant cancer.

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Despite numerous advances in cancer radiotherapy, tumor radioresistance remain one of the major challenges limiting treatment efficacy of radiotherapy. Conventional strategies to overcome radioresistance involve understanding the underpinning molecular mechanisms, and subsequently using combinatorial treatment strategies involving radiation and targeted drug combinations against these radioresistant tumors. These strategies exploit and target the molecular fingerprint and vulnerability of the radioresistant clones to achieve improved efficacy in tumor eradication. However, conventional drug-screening approaches for the discovery of new drug combinations have been proven to be inefficient, limited and laborious. With the increasing availability of computational resources in recent years, novel approaches such as Quadratic Phenotypic Optimization Platform (QPOP), CURATE.AI and Drug Combination and Prediction and Testing (DCPT) platform have emerged to aid in drug combination discovery and the longitudinally optimized modulation of combination therapy dosing. These platforms could overcome the limitations of conventional screening approaches, thereby facilitating the discovery of more optimal drug combinations to improve the therapeutic ratio of combinatorial treatment. The use of better and more accurate models and methods with rapid turnover can thus facilitate a rapid translation in the clinic, hence, resulting in a better patient outcome. Here, we reviewed the clinical observations, molecular mechanisms and proposed treatment strategies for tumor radioresistance and discussed how novel approaches may be applied to enhance drug combination discovery, with the aim to further improve the therapeutic ratio and treatment efficacy of radiotherapy against radioresistant cancers.

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Cellular radioresistance is one of the major obstacles to the effectiveness of cancer radiotherapy. In an attempt to elucidate the implication of HIF-1α and miR-17-92 expressions in refractory radioresistant cells and also in order to study the potential applications of these molecules as novel therapeutic modalities to overcome radioresistant cancers, the current study was conducted. Clinically relevant radioresistant (CRR) cells from human cancer cell lines were established by exposing to long-term fractionated radiation of X-rays. Correspondingly, microarray analysis and real time RT-PCR were performed to find miRNA involved in the CRR phenotype. HIF-1α was down-regulated and miR17-92 cluster was overexpressed in CRR cells by transfection. The expression of miR 17-3p was inhibited by specific inhibitors and miR 19a was enforced by mimics, respectively in parental cells. Overexpression of HIF-1α in parental cells or down regulation of HIF-1α in CRR cells were not involved in radioresistance. However, when HIF-1α was genetically modified to constitutively express under normoxia condition, it was rendered for protection to cells. Exogenous overexpression of miR 17-92 cluster in CRR cells resulted in abolition of HIF-1α expression and restored sensitizations to ionizing radiation. Attenuated expression of miR-17-3p in parental cells protected them from irradiation. Overall, fine-tune deregulation of miR 17-92 cluster in CRR cells might account for the accumulation of HIF-1α in the CRR cells following exposure to irradiation.

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Radiotherapy is the biggest force acting behind cancer treatment, yet the vast majority of patients get only modest benefit. The successive failure of targeted therapies in radiotherapy lies in the non-discriminative killing of both normal and cancer cells. However, there is still a reason for optimism due to recent advancement made in cancer biology which unrevealed many new deregulated pathways in cancer and their response towards drug and radiation. In this review, we comprehensively discussed novel and promising druggable target which can be exploited for tumor radiosensitization in addition to normal tissue radioprotection in radiotherapy, for better tumor controllability and patient quality of life. In the last part, we also discussed the radiation countermeasure agents in brief.

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