Abstract
The pharmacological inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) have reached the first milestone toward their inclusion in the arsenal of anti-cancer drugs by showing consistent benefits in clinical trials against BRCA-mutant cancers that are deficient in the homologous recombination repair (HRR) of DNA double strand breaks (DSB) (1, 2). PARP inhibitors (PARPi) also potentiate therapeutic efficacy of ionizing radiation and some chemotherapeutic agents (1). These effects of PARPi were initially linked to inhibition of the role of PARP-1 in base excision repair (BER) of DNA damaged by endogenous or exogenous agents, resulting in accumulation of single strand breaks (SSB), which upon conversion to toxic DSB lesions would kill cancer cells deficient in DSB repair (1, 3, 4). However, PARPi lethality in HRR-deficient cancers can also be explained by other mechanisms not involving a direct effect of PARPi on BER [reviewed in Ref. (5, 6)]. In addition, therapeutic benefits of PARPi with agents such as carboplatin in HRR-proficient and -deficient tumors [reviewed in Ref. (1, 7)], simply cannot be explained by BER inhibitory effect of PARPi. Therefore, PARPi are like magic bullets that can kill cancer cells under different circumstances, but to comprehend their global scope and limitations, here we discuss the full range of their targets and the possible impact of broad specificity of current PARPi during prolonged therapy of cancer patients.
Highlights
MECHANISMS OF ACTION OF PARP inhibitors (PARPi) IN CANCER THERAPY: MAGIC BULLETS BUT MOVING TARGETS It is not surprising that the mechanism of action of PARPi in killing cancer cells still remains an open question, because its principal target PARP-1 is a multifunctional protein implicated in various cellular responses to DNA damage ranging from different pathways of DNA repair and cell death to stress signaling, transcription, and genomic stability [8, 9], all of which could be affected by PARPi and influence outcome of cancer therapies
base excision repair (BER)/homologous recombination repair (HRR) NEXUS FOR SYNTHETIC LETHALITY OF PARPi IN BRCA-MUTANT CANCERS It was first demonstrated by two teams [3, 4] that two individually non-lethal conditions, i.e., PARPi-mediated inhibition of PARP-1 and BRCA mutationinduced HRR deficiency in cancer cell, would become synthetic lethal when combined in a single cell [reviewed in Ref. [1, 5, 10, 11]] (Figure 1A)
(i) PARPi could be trapping PARP-1 or PARP-2 to single strand breaks (SSB) with resultant PARP-SSB complex that would be more toxic than unrepaired SSB or even knockdown of PARPs [5, 12]. (ii) PARPi could act via upregulation of non-homologous end-joining (NHEJ) pathway, which would presumably cause genomic instability and eventual lethality [13]. (iii) PARPi could suppress the role of PARP-1 in reactivating DNA replication forks [5]
Summary
MECHANISMS OF ACTION OF PARPi IN CANCER THERAPY: MAGIC BULLETS BUT MOVING TARGETS It is not surprising that the mechanism of action of PARPi in killing cancer cells still remains an open question, because its principal target PARP-1 is a multifunctional protein implicated in various cellular responses to DNA damage ranging from different pathways of DNA repair and cell death to stress signaling, transcription, and genomic stability [8, 9], all of which could be affected by PARPi and influence outcome of cancer therapies. When PARPi suppress the role of PARP-1 in BER, the unrepaired SSB would accumulate and collapse the DNA replication fork to form potentially lethal DSB.
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