Ligands stimulating antitumour immunity as the next G-quadruplex challenge

Abstract

G-quadruplex (G4) binders have been investigated to discover new anticancer drugs worldwide in past decades. As these ligands are generally not highly cytotoxic, the discovery rational was mainly based on increasing the cell-killing potency. Nevertheless, no G4 binder has been shown yet to be effective in cancer patients. Here, G4 binder activity at low dosages will be discussed as a critical feature to discover ligands with therapeutic effects in cancer patients. Specific effects of G4 binders al low doses have been reported to occur in cancer and normal cells. Among them, genome instability and the stimulation of cytoplasmic processes related to autophagy and innate immune response open to the use of G4 binders as immune-stimulating agents. Thus, we propose a new rational of drug discovery, which is not based on cytotoxic potency but rather on immune gene activation at non-cytotoxic dosage.

Balancing Affinity, Selectivity, and Cytotoxicity of Hydrazone-Based G-Quadruplex Ligands for Activation of Interferon β Genes in Cancer Cells

“… 29 , 30 Even though the definition of the mechanism likely needs future investigations, however, the activation of other cytoplasmic signaling pathways may affect the recognition of micronuclei and activation of the STING pathway. 5 , 29 , 30 Autophagic processes are known to be activated by G4 binders 3 , 31 , 32 and can regulate the STING pathway through recycling micronuclei and DNA by forming autophagosomes. 33 , 34 Interestingly, autophagic gene pathways were not activated at high levels in MCF-7 cells treated with PDS , which can activate at very high levels the IFN-B gene and other genes stimulated by IFN-B.…”

“… 1 − 4 Despite the large number of specific ligands developed, none has however shown efficacy in cancer patients and very few have reached early phases of clinical trials. 5 , 6 In line with the standard drug discovery rationale, several laboratories have previously searched for G4 binders with a high cell-killing potency. 1 − 5 Interestingly, we have recently demonstrated that the G4 binders pyridostatin ( PDS ) and PhenDC3 can effectively elicit an innate immune gene response [activation of interferon β (IFN-B) gene and IFN-B-dependent pathways] in human cancer cells, mediated by micronuclei accumulation at non-cytotoxic concentrations.…”

“…Thus, our recent findings 7 indicate that G4 ligands may be exploited as cytostatic immune-stimulating agents for anticancer immune-therapeutic combinations. 5 In particular, G4 binders can increase micronuclei, 7 , 13 , 14 which can be a source of cytoplasmic DNA that is able to induce the cGAS–STING pathway and activate innate immune genes. 7 , 15 , 16 However, the relationships among G4 affinity/selectivity, cell-killing potency, and genome instability determining a high level of immune gene activation by G4 ligands remains to be established.…”

“…G-quadruplex (G4) ligands are actively investigated to discover new effective anticancer drugs as G4s, non-canonical DNA structures, are considered promising targets. − Despite the large number of specific ligands developed, none has however shown efficacy in cancer patients and very few have reached early phases of clinical trials. , In line with the standard drug discovery rationale, several laboratories have previously searched for G4 binders with a high cell-killing potency. − Interestingly, we have recently demonstrated that the G4 binders pyridostatin ( PDS ) and PhenDC3 can effectively elicit an innate immune gene response [activation of interferon β (IFN-B) gene and IFN-B-dependent pathways] in human cancer cells, mediated by micronuclei accumulation at non-cytotoxic concentrations . As recent advances clearly point to the potential of harnessing innate immunity for cancer immunotherapy, − non-cytotoxic immune-modulators may optimize immunotherapy in unresponsive cancers while having a marginal toxicity against proliferating normal cells.…”

“…As recent advances clearly point to the potential of harnessing innate immunity for cancer immunotherapy, − non-cytotoxic immune-modulators may optimize immunotherapy in unresponsive cancers while having a marginal toxicity against proliferating normal cells. Thus, our recent findings indicate that G4 ligands may be exploited as cytostatic immune-stimulating agents for anticancer immune-therapeutic combinations . In particular, G4 binders can increase micronuclei, ,, which can be a source of cytoplasmic DNA that is able to induce the cGAS–STING pathway and activate innate immune genes. ,, However, the relationships among G4 affinity/selectivity, cell-killing potency, and genome instability determining a high level of immune gene activation by G4 ligands remains to be established.…”