Browsing by Author "Huang, Xiumei"
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Item Augmented Concentration of Isopentyl-Deoxynyboquinone in Tumors Selectively Kills NAD(P)H Quinone Oxidoreductase 1-Positive Cancer Cells through Programmed Necrotic and Apoptotic Mechanisms(MDPI, 2023-12-14) Wang, Jiangwei; Su, Xiaolin; Jiang, Lingxiang; Boudreau, Matthew W.; Chatkewitz, Lindsay E.; Kilgore, Jessica A.; Zahid, Kashif Rafiq; Williams, Noelle S.; Chen, Yaomin; Liu, Shaohui; Hergenrother, Paul J.; Huang, Xiumei; Biochemistry and Molecular Biology, School of MedicineLung and breast cancers rank as two of the most common and lethal tumors, accounting for a substantial number of cancer-related deaths worldwide. While the past two decades have witnessed promising progress in tumor therapy, developing targeted tumor therapies continues to pose a significant challenge. NAD(P)H quinone oxidoreductase 1 (NQO1), a two-electron reductase, has been reported as a promising therapeutic target across various solid tumors. β-Lapachone (β-Lap) and deoxynyboquinone (DNQ) are two NQO1 bioactivatable drugs that have demonstrated potent antitumor effects. However, their curative efficacy has been constrained by adverse effects and moderate lethality. To enhance the curative potential of NQO1 bioactivatable drugs, we developed a novel DNQ derivative termed isopentyl-deoxynyboquinone (IP-DNQ). Our study revealed that IP-DNQ treatment significantly increased reactive oxygen species generation, leading to double-strand break (DSB) formation, PARP1 hyperactivation, and catastrophic energy loss. Notably, we discovered that this novel drug induced both apoptosis and programmed necrosis events, which makes it entirely distinct from other NQO1 bioactivatable drugs. Furthermore, IP-DNQ monotherapy demonstrated significant antitumor efficacy and extended mice survival in A549 orthotopic xenograft models. Lastly, we identified that in mice IP-DNQ levels were significantly elevated in the plasma and tumor compared with IB-DNQ levels. This study provides novel preclinical evidence supporting IP-DNQ efficacy in NQO1+ NSCLC and breast cancer cells.Item Critical Role of Novel O-GlcNAcylation of S550 and S551 on the p65 Subunit of NF-κB in Pancreatic Cancer(MDPI, 2023-09-27) Motolani, Aishat; Martin, Matthew; Wang, Benlian; Jiang, Guanglong; Alipourgivi, Faranak; Huang, Xiumei; Safa, Ahmad; Liu, Yunlong; Lu, Tao; Pharmacology and Toxicology, School of MedicinePancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with a mere 5-year survival of ~10%. This highlights the urgent need for innovative treatment options for PDAC patients. The nuclear factor κB (NF-κB) is a crucial transcription factor that is constitutively activated in PDAC. It mediates the transcription of oncogenic and inflammatory genes that facilitate multiple PDAC phenotypes. Thus, a better understanding of the mechanistic underpinnings of NF-κB activation holds great promise for PDAC diagnosis and effective therapeutics. Here, we report a novel finding that the p65 subunit of NF-κB is O-GlcNAcylated at serine 550 and 551 upon NF-κB activation. Importantly, the overexpression of either serine-to-alanine (S-A) single mutant (S550A or S551A) or double mutant (S550A/S551A) of p65 in PDAC cells impaired NF-κB nuclear translocation, p65 phosphorylation, and transcriptional activity, independent of IκBα degradation. Moreover, the p65 mutants downregulate a category of NF-κB-target genes, which play a role in perpetuating major cancer hallmarks. We further show that overexpression of the p65 mutants inhibited cellular proliferation, migration, and anchorage-independent growth of PDAC cells compared to WT-p65. Collectively, we discovered novel serine sites of p65 O-GlcNAcylation that drive NF-κB activation and PDAC phenotypes, thus opening new avenues by inhibiting the NF-κB O-GlcNAcylation enzyme, O-GlcNAc transferase (OGT), for PDAC treatment in the future.Item Inhibition of PRMT5 by market drugs as a novel cancer therapeutic avenue(Elsevier, 2023-01) Prabhu, Lakshmi; Martin, Matthew; Chen, Lan; Demir, Özlem; Jin, Jiamin; Huang, Xiumei; Motolani, Aishat; Sun, Mengyao; Jiang, Guanglong; Nakshatri, Harikrishna; Fishel, Melissa L.; Sun, Steven; Safa, Ahmad; Amaro, Rommie E.; Kelley, Mark R.; Liu, Yunlong; Zhang, Zhong-Yin; Lu, Tao; Radiation Oncology, School of MedicineMarket drugs, such as Food and Drug Administration (FDA) or European Medicines Agency (EMA)-approved drugs for specific indications provide opportunities for repurposing for newer therapeutics. This potentially saves resources invested in clinical trials that verify drug safety and tolerance in humans prior to alternative indication approval. Protein arginine methyltransferase 5 (PRMT5) overexpression has been linked to promoting the tumor phenotype in several cancers, including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and breast cancer (BC), making PRMT5 an important target for cancer therapy. Previously, we showed that PRMT5-mediated methylation of the nuclear factor (NF)-κB, partially contributes to its constitutive activation observed in cancers. In this study, we utilized an AlphaLISA-based high-throughput screening method adapted in our lab, and identified one FDA-approved drug, Candesartan cilexetil (Can, used in hypertension treatment) and one EMA-approved drug, Cloperastine hydrochloride (Clo, used in cough treatment) that had significant PRMT5-inhibitory activity, and their anti-tumor properties were validated using cancer phenotypic assays . Furthermore, PRMT5 selective inhibition of methyltransferase activity was confirmed by reduction of both NF-κB methylation and its subsequent activation upon drug treatment. Using prediction, we identified critical residues on PRMT5 targeted by these drugs that may interfere with its enzymatic activity. Finally, Clo and Can treatment have exhibited marked reduction in tumor growth . Overall, we provide basis for pursuing repurposing Clo and Can as anti-PRMT5 cancer therapies. Our study offers potential safe and fast repurposing of previously unknown PRMT5 inhibitors into clinical practice.Item Isopentyl-Deoxynboquinone Induces Mitochondrial Dysfunction and G2/M Phase Cell Cycle Arrest to Selectively Kill NQO1-Positive Pancreatic Cancer Cells(Mary Ann Liebert, Inc., 2024) Jiang, Lingxiang; Liu, Yingchun; Tumbath, Soumya; Boudreau, Matthew W.; Chatkewitz, Lindsay E.; Wang, Jiangwei; Su, Xiaolin; Zahid, Kashif Rafiq; Li, Katherine; Chen, Yaomin; Yang, Kai; Hergenrother, Paul J.; Huang, Xiumei; Radiation Oncology, School of MedicineAims: Pancreatic cancer is among the top five leading causes of cancer-related deaths worldwide, with poor overall survival rates. Current therapies for pancreatic cancer lack tumor specificity, resulting in harmful effects on normal tissues. Therefore, developing tumor-specific agents for the treatment of pancreatic cancer is critical. NAD(P)H:quinone oxidoreductase 1 (NQO1), highly expressed in pancreatic cancers but not in associated normal tissues, makes NQO1 bioactivatable drugs a potential therapy for selectively killing NQO1-positive cancer cells. Our previous studies have revealed that the novel NQO1 bioactivatable drug deoxynyboquinone (DNQ) is 10-fold more potent than the prototypic NQO1 bioactivatable drug β-lapachone in killing of NQO1-positive cancer cells. However, DNQ treatment results in high-grade methemoglobinemia, a significant side effect that limits clinical development. Results: Here, we report for the first time on a DNQ derivative, isopentyl-deoxynboquinone (IP-DNQ), which selectively kills pancreatic ductal adenocarcinoma (PDAC) cells in an NQO1-dependent manner with equal potency to the parent DNQ. IP-DNQ evokes massive reactive oxygen species (ROS) production and oxidative DNA lesions that result in poly(ADP-ribose)polymerase-1 (PARP1) hyperactivation, mitochondrial catastrophe, and G2/M phase cell cycle arrest, leading to apoptotic and necrotic programmed cell death. Importantly, IP-DNQ treatment causes only mild methemoglobinemia in vivo, with a threefold improvement in the maximum tolerated dose (MTD) compared with DNQ, while it significantly suppresses tumor growth and extends the life span of mice in subcutaneous and orthotopic pancreatic cancer xenograft models. Innovation and Conclusion: Our study demonstrates that IP-DNQ is a promising therapy for NQO1-positive pancreatic cancers and may enhance the efficacy of other anticancer drugs. IP-DNQ represents a novel approach to treating pancreatic cancer with the potential to improve patient outcomes.Item KP372-1-Induced AKT Hyperactivation Blocks DNA Repair to Synergize With PARP Inhibitor Rucaparib Inhibiting FOXO3a/GADD45α Pathway(Frontiers, 2022-09) Jiang, Lingxiang; Liu, Yingchun; Su, Xiaolin; Wang, Jiangwei; Zhao, Ye; Tumbath, Soumya; Kilgore, Jessica A.; Williams, Noelle S.; Chen, Yaomin; Wang, Xiaolei; Mendonca, Marc S.; Lu, Tao; Fu, Yang-Xin; Huang, Xiumei; Radiation Oncology, School of MedicinePoly (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 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 Ca-dependent autophagy and apoptosis. Moreover, pretreatment of cells with BAPTA-AM, a cytosolic Ca 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 solid tumors that may broaden the clinical utility of PARPi.Item Neutrophils: Musketeers against immunotherapy(Frontiers, 2022-08) Zahid, Kashif Rafiq; Raza, Umar; Tumbath, Soumya; Jiang, Lingxiang; Xu, Wenjuan; Huang, Xiumei; Radiation Oncology, School of MedicineNeutrophils, 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.Item NQO1 targeting prodrug triggers innate sensing to overcome checkpoint blockade resistance(Springer Nature, 2019-07-19) Li, Xiaoguang; Liu, Zhida; Zhang, Anli; Han, Chuanhui; Shen, Aijun; Jiang, Lingxiang; Boothman, David A.; Qiao, Jian; Wang, Yang; Huang, Xiumei; Fu, Yang-Xin; Radiation Oncology, IU School of MedicineLack of proper innate sensing inside tumor microenvironment (TME) limits T cell-targeted immunotherapy. NAD(P)H:quinone oxidoreductase 1 (NQO1) is highly enriched in multiple tumor types and has emerged as a promising target for direct tumor-killing. Here, we demonstrate that NQO1-targeting prodrug β-lapachone triggers tumor-selective innate sensing leading to T cell-dependent tumor control. β-Lapachone is catalyzed and bioactivated by NQO1 to generate ROS in NQO1high tumor cells triggering oxidative stress and release of the damage signals for innate sensing. β-Lapachone-induced high mobility group box 1 (HMGB1) release activates the host TLR4/MyD88/type I interferon pathway and Batf3 dendritic cell-dependent cross-priming to bridge innate and adaptive immune responses against the tumor. Furthermore, targeting NQO1 is very potent to trigger innate sensing for T cell re-activation to overcome checkpoint blockade resistance in well-established tumors. Our study reveals that targeting NQO1 potently triggers innate sensing within TME that synergizes with immunotherapy to overcome adaptive resistance.Item NQO1-Bioactivatable Therapeutics as Radiosensitizers for Cancer Treatment(IntechOpen, 2020) Singh, Naveen; Motea, Edward A.; Huang, Xiumei; Starcher, Colton L.; Silver, Jayne; Yeh, I-Ju; Pay, S. Louise; Su, Xiaolin; Russ, Kristen A.; Boothman, David A.; Bey, Erik A.; Biochemistry and Molecular Biology, School of MedicineDeveloping cancer therapeutics that radiosensitize in a tumor-selective manner remains an ideal. We developed a novel means of radiosensitization, exploiting NAD(P)H:Quinone Oxidoreductase 1 (NQO1) overexpression, and lowered catalase expression in solid human tumors using NQO1-bioactivatable drugs. Non-small cell lung (NSCLC), pancreatic (PDAC), prostate, and breast cancers overexpress NQO1. Ionizing radiation (IR) creates a spectrum of DNA lesions, including lethal DNA double-strand breaks (DSBs), and mutagenic but rarely lethal altered DNA bases and DNA single-strand breaks (SSBs). NQO1-bioactivatable drugs (e.g., β-lapachone and deoxynyboquiones) also promote abasic DNA lesions and SSBs. These hyperactivate poly (ADP-ribose) polymerase 1 (PARP1) and dramatically increase calcium release from the endoplasm reticulum (ER). Exposure of human cancer cells overexpressing NQO1 to NQO1-bioactivatable drugs immediately following IR, therefore, hyperactivates PARP1 synergistically, which in turn depletes NAD+ and ATP, inhibiting DSB repair. Ultimately, this leads to cell death. Combining IR with NQO1-bioactivatable drugs allows for a reduction in drug dose. Similarly, a lower IR dose can be used in combination with the drug, reducing the effects of IR on normal tissue. The combination treatment is effective in preclinical animal models with NSCLC, prostate, and head and neck xenografts, indicating that clinical trials are warranted.Item NQO1-Bioactivatable Therapeutics as Radiosensitizers for Cancer Treatment(InTechOpen, 2020-02-13) Singh, Naveen; Motea, Edward A.; Huang, Xiumei; Starcher, Colton L.; Silver, Jayne; Yeh, I.-Ju; Pay, S. Louise; Su, Xiaolin; Russ, Kristen A.; Boothman, David A.; Bey, Erik A.; Biochemistry and Molecular Biology, School of MedicineDeveloping cancer therapeutics that radiosensitize in a tumor-selective manner remains an ideal. We developed a novel means of radiosensitization, exploiting NAD(P)H:Quinone Oxidoreductase 1 (NQO1) overexpression, and lowered catalase expression in solid human tumors using NQO1-bioactivatable drugs. Non-small cell lung (NSCLC), pancreatic (PDAC), prostate, and breast cancers overexpress NQO1. Ionizing radiation (IR) creates a spectrum of DNA lesions, including lethal DNA double-strand breaks (DSBs), and mutagenic but rarely lethal altered DNA bases and DNA single-strand breaks (SSBs). NQO1-bioactivatable drugs (e.g., β-lapachone and deoxynyboquiones) also promote abasic DNA lesions and SSBs. These hyperactivate poly (ADP-ribose) polymerase 1 (PARP1) and dramatically increase calcium release from the endoplasm reticulum (ER). Exposure of human cancer cells overexpressing NQO1 to NQO1-bioactivatable drugs immediately following IR, therefore, hyperactivates PARP1 synergistically, which in turn depletes NAD+ and ATP, inhibiting DSB repair. Ultimately, this leads to cell death. Combining IR with NQO1-bioactivatable drugs allows for a reduction in drug dose. Similarly, a lower IR dose can be used in combination with the drug, reducing the effects of IR on normal tissue. The combination treatment is effective in preclinical animal models with NSCLC, prostate, and head and neck xenografts, indicating that clinical trials are warranted.Item NQO1-dependent, tumor-selective radiosensitization of non-small cell lung cancers(American Association for Cancer Research, 2019-04-15) Motea, Edward A.; Huang, Xiumei; Singh, Naveen; Kilgore, Jessica; Williams, Noelle; Xie, Xian-Jin; Gerber, David E.; Beg, Muhammad Shaalan; Bey, Erik A.; Boothman, David A.; Biochemistry and Molecular Biology, School of MedicinePurpose: Development of tumor-specific therapies for the treatment of recalcitrant non-small cell lung cancers (NSCLCs) are urgently needed. Here, we investigated the ability of ß-lapachone (ß-lap, ARQ761 in clinical form) to selectively potentiate the effects of ionizing radiation (IR, 1–3 Gy) in NSCLCs that over-express NAD(P)H:Quinone Oxidoreductase 1 (NQO1). Experimental Design: The mechanism of lethality of low dose IR in combination with sublethal doses of ß-lap were evaluated in NSCLC lines in vitro and validated in subcutaneous and orthotopic xenograph models in vivo. Pharmacokinetics and pharmacodynamics (PK/PD) studies comparing single versus co-treatments were performed to validate therapeutic efficacy and mechanism of action. Results: ß-Lap administration after IR treatment hyperactivated PARP, greatly lowered NAD+/ATP levels, and increased DSB lesions over time in vitro. Radiosensitization of orthotopic, as well as subcutaneous, NSCLCs occurred with high apparent cures (>70%), even though 1/8 ß-lap doses reach subcutaneous versus orthotopic tumors. No methemoglobinemia or long-term toxicities were noted in any normal tissues, including mouse liver that expresses the highest level of NQO1 (~12 Units) of any normal tissue. PK/PD responses confirm that IR + ß-lap treatments hyperactivate PARP activity, greatly lower NAD+/ATP levels and dramatically inhibit DSB repair in exposed NQO1+ cancer tissue, while low NQO1 levels and high levels of Catalase in associated normal tissue were protective. Conclusion: Our data suggest that combination of sublethal doses of ß-lap and IR is a viable approach to selectively treat NQO1-overexpressing NSCLC and warrant a clinical trial using low-dose IR + ß-lapachone against patients with NQO1+ NSCLCs.