No abstract

Neutrophils, the most copious leukocytes in human blood, play a critical role in tumorigenesis, cancer progression, and immune suppression. Recently, neutrophils have attracted the attention of researchers, immunologists, and oncologists because of their potential role in orchestrating immune evasion in human diseases including cancer, which has led to a hot debate redefining the contribution of neutrophils in tumor progression and immunity. To make this debate fruitful, this review seeks to provide a recent update about the contribution of neutrophils in immune suppression and tumor progression. Here, we first described the molecular pathways through which neutrophils aid in cancer progression and orchestrate immune suppression/evasion. Later, we summarized the underlying molecular mechanisms of neutrophil-mediated therapy resistance and highlighted various approaches through which neutrophil antagonism may heighten the efficacy of the immune checkpoint blockade therapy. Finally, we have highlighted several unsolved questions and hope that answering these questions will provide a new avenue toward immunotherapy revolution.

<p class="Default">Zingiberaceae family members are well known for their ethnobotanical diversity and medicinal importance.  This study aimed to evaluate total phenolic content, antioxidant and antiproliferative capacity of five different organic solvent extracts prepared from the rhizomes of <em>Curcuma mutabilis</em> (CM)<em>, Curcuma haritha </em>(CH)<em>, Curcuma neilgherrensis</em> (CN) and<em> Zingiber anamalayanum</em> (ZA), four hitherto unexplored Zingiberaceae species.  Folin-<span class="tgc">Ciocalteu method and </span>DPPH radical scavenging assay were used to determine respectively the total phenolic content and<span class="tgc"> antioxidant </span>capacity.<span class="tgc">  </span>The antiproliferative activity of the extracts were tested against four human cancer cell lines –  K562,  REH, Nalm6 and MCF7 to ascertain the IC₅₀ values.  Based on total phenolic content, extracts were classified into high-H (&gt; 150 mg GAE/g), medium-M (50-150 mg GAE/g) and low-L (&lt; 50 mg GAE/g) categories.  Likewise, percentages of DPPH scavenging activity of extracts were also grouped into high-H (&gt; 50%), medium-M (25 – 50%) and low-L (&lt; 25%) categories.  Ten of the twenty extracts exhibited strong cytotoxicity with an IC₅₀value less than 30 μg/mL.  To our knowledge, this is the first report on quantitative assessment of total phenolics, antioxidant and antiproliferative potential of organic solvent extracts of rhizomes from the above mentioned plants.</p>

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have exhibited great promise in the treatment of tumors with homologous recombination (HR) deficiency, however, PARPi resistance, which ultimately recovers DNA repair and cell progress, has become an enormous clinical challenge. Recently, KP372-1 was identified as a novel potential anticancer agent that targeted the redox enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), to induce extensive reactive oxygen species (ROS) generation that amplified DNA damage, leading to cancer cell death. To overcome PARPi resistance and expand its therapeutic utility, we investigated whether a combination therapy of a sublethal dose of KP372-1 with a nontoxic dose of PARPi rucaparib would synergize and enhance lethality in NQO1 over-expressing cancers. We reported that the combination treatment of KP372-1 and rucaparib induced a transient and dramatic AKT hyperactivation that inhibited DNA repair by regulating FOXO3a/GADD45α pathway, which enhanced PARPi lethality and overcame PARPi resistance. We further found that PARP inhibition blocked KP372-1-induced PARP1 hyperactivation to reverse NAD+/ATP loss that promoted Ca2+-dependent autophagy and apoptosis. Moreover, pretreatment of cells with BAPTA-AM, a cytosolic Ca2+ chelator, dramatically rescued KP372-1- or combination treatment-induced lethality and significantly suppressed PAR formation and γH2AX activation. Finally, we demonstrated that this combination therapy enhanced accumulation of both agents in mouse tumor tissues and synergistically suppressed tumor growth in orthotopic pancreatic and non-small-cell lung cancer xenograft models. Together, our study provides novel preclinical evidence for new combination therapy in NQO1+ solid tumors that may broaden the clinical utility of PARPi.