Poly-(ADP-ribose) polymerase 1 (PARP1) is commonly known for its vital role in DNA damage response and repair. However, its enzymatic activity has been linked to a plethora of physiological and pathophysiological transactions ranging from cellular proliferation, survival and death. For instance, malignancies with BRCA1/2 mutations heavily rely on PARP activity for survival. Thus, the use of PARP inhibitors is a well-established intervention in these types of tumors. However, recent studies indicate that the therapeutic potential of attenuating PARP1 activity in recalcitrant tumors, especially where PARP1 is aberrantly overexpressed and hyperactivated, may extend its therapeutic utility in wider cancer types beyond BRCA-deficiency. Here, we discuss treatment strategies to expand the tumor-selective therapeutic application of PARP inhibitors and novel approaches with predictive biomarkers to perturb NAD+ levels and hyperPARylation that inactivate PARP in recalcitrant tumors. We also provide an overview of genetic alterations that transform non-BRCA mutant cancers to a state of “BRCAness” as potential biomarkers for synthetic lethality with PARP inhibitors. Finally, we discuss a paradigm shift for the use of novel PARP inhibitors outside of cancer treatment, where it has the potential to rescue normal cells from severe oxidative damage during ischemia-reperfusion injury induced by surgery and radiotherapy.

Ionizing radiation (IR) creates lethal DNA damage that can effectively kill tumor cells. However, the high dose required for a therapeutic outcome also damages healthy tissue. Thus, a therapeutic strategy with predictive biomarkers to enhance the beneficial effects of IR allowing a dose reduction without losing efficacy is highly desirable. NAD(P)H:quinone oxidoreductase 1 (NQO1) is overexpressed in the majority of recalcitrant solid tumors in comparison with normal tissue. Studies have shown that NQO1 can bioactivate certain quinone molecules (e.g., ortho-naphthoquinone and β-lapachone) to induce a futile redox cycle leading to the formation of oxidative DNA damage, hyperactivation of poly(ADP-ribose) polymerase 1 (PARP1), and catastrophic depletion of NAD + and ATP, which culminates in cellular lethality via NAD + -Keresis. However, NQO1-bioactivatable drugs induce methemoglobinemia and hemolytic anemia at high doses. To circumvent this, NQO1-bioactivatable agents have been shown to synergize with PARP1 inhibitors, pyrimidine radiosensitizers, and IR. This therapeutic strategy allows for a reduction in the dose of the combined agents to decrease unwanted side effects by increasing tumor selectivity. In this review, we discuss the mechanisms of radiosensitization between NQO1-bioactivatable drugs and IR with a focus on the involvement of base excision repair (BER). This combination therapeutic strategy presents a unique tumor-selective and minimally toxic approach for targeting solid tumors that overexpress NQO1.

Objective: To optimize the extraction parameters for determining the highest yield of Total Flavonoids from Gardenia gummifera gum resin. Methods:In the present study, response surface methodology (RSM) with three level Box Behenken design (BBD) was performed to optimize extraction parameters for total flavonoids. Solvent concentration(A), extraction time (B) and extraction temperature(C) were considered for single factor experiment. Results:The highest flavonoid concentration was obtained with acetone 45.00% v/v, time 101.46 min, temperature 41.57 °C. The average experimental TFC under optimal conditions was 161.14 mg/g which was in close agreement with the predicted value of 163.42 mg/g. Conclusion:RSM-BBD is successfully applied in optimizing extraction conditions for extraction of total flavonoids from G. gummifera gum resin.

The overall prognosis for solid tumors overexpressing mesenchymal‐epithelial transition factor (cMET) receptor tyrosine kinase and NADPH:Quinone oxidoreductase 1 (NQO1) is poor, and innovative treatment strategies that selectively target these cancers are critically needed. Recent studies have implicated cMET in the activation of PARP1, a critical factor involved in DNA damage response and repair. Therefore, targeting cMET is an attractive strategy for cancer therapy. However, the overall efficacies of cMET inhibitors and NQO1 bioactivable agents are limited due to dose‐limiting toxicities and lack of tumor selectivity at high concentrations as a monotherapy. Here, we report that the combination treatment with sublethal doses of cMET inhibitors (some in clinical trials and FDA‐approved) and β‐lapachone (β‐lap, an NQO1‐bioactivatable drug in clinical trials) induced synergistic lethality in cancer cells in an NQO1‐dependent manner. Mechanistically, a sublethal dose of β‐lap creates reactive oxygen species (ROS) that damage DNA nucleobases (e.g., 8‐oxoguanine) but rapidly gets repaired by the ability of ROS‐activated cMET to enhance PARP1 activity for efficient DNA damage repair in NQO1+ cells. Thus, β‐lap in combination with cMET inhibition elevated DNA damage by compromising DNA repair, increased double‐strand break (DSB) formation and promoted tumor selective apoptosis in NQO1+cancer cells. We further determined that the combination treatment significantly inhibit tumor growth in 3D spheroids. Our results add a new strategy for personalized therapy: the targeting of cMET in NQO1+ cancers to potentiate the toxic effects of sub‐lethal doses of NQO1‐bioativatable agents and cMET inhibitors.