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Further Investigation of the Potential Anti-Neoplastic, Anti-Inflammatory And bioRxiv preprint doi: https://doi.org/10.1101/767392; this version posted September 12, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Further investigation of the potential anti-neoplastic, anti-inflammatory and 2 immunomodulatory actions of phenoxybenzamine using the Broad Institute CLUE 3 platform. 4 5 Mario A. Inchiosa, Jr. 6 Departments of Pharmacology and Anesthesiology, New York Medical College, Valhalla, NY 7 10595 8 9 Short title: Gene expression profiling of phenoxybenzamine in the Broad Institute CLUE 10 platform. 11 12 Keywords: Phenoxybenzamine; gene expression signature predictions; anti-tumor mechanisms; 13 histone deacetylase inhibitors. 14 15 16 17 18 19 1 bioRxiv preprint doi: https://doi.org/10.1101/767392; this version posted September 12, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 20 21 Abstract: 22 Previous clinical studies with the FDA-approved alpha-adrenergic antagonist, 23 phenoxybenzamine, showed apparent efficacy to reverse the symptoms and disabilities of the 24 neuropathic condition, Complex Regional Pain Syndrome; also, the anatomic spread and 25 intensity of this syndrome has a proliferative character and it was proposed that 26 phenoxybenzamine may have an anti-inflammatory, immunomodulatory mode of action. A 27 previous study gave evidence that phenoxybenzamine had anti-proliferative activity in 28 suppression of growth in several human tumor cell cultures. The same report demonstrated that 29 the drug possessed significant histone deacetylase inhibitory activity. Utilizing the 30 Harvard/Massachusetts Institute of Technology Broad Institute genomic database, CLUE, the 31 present study suggests that the gene expression signature of phenoxybenzamine in malignant cell 32 lines is consistent with anti-inflammatory/immunomodulatory activity and suppression of tumor 33 expansion by several possible mechanisms of action. Of particular note, phenoxybenzamine 34 demonstrated signatures that were highly similar to those with glucocorticoid agonist activity. 35 Also, gene expression signatures of phenoxbenzamine were consistent with several agents in 36 each case that were known to suppress tumor proliferation, notably, protein kinase C inhibitors, 37 Heat Shock Protein inhibitors, epidermal growth factor receptor inhibitors, and glycogen 38 synthase kinase inhibitors. Searches in CLUE also confirmed the earlier observations of strong 39 similarities between gene expression signatures of phenoxybenzamine and several histone 40 deacetylase inhibitors. 41 42 2 bioRxiv preprint doi: https://doi.org/10.1101/767392; this version posted September 12, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 43 44 1. Introduction 45 A previous study explored a possible anti-proliferative capacity of the drug, 46 phenoxybenzamine (PBZ), as a basis for its apparent therapeutic potential in the treatment of 47 chronic neuropathic pain in the Complex Regional Pain Syndrome (CRPS) (1). The 48 BroadBuild02, Broad Institute Harvard/Massachusetts Institute of Technology (MIT) Molecular 49 Signature Database (MSigDB) and the associated Connectivity Map (CMap) software were 50 explored for a possible basis for this effect (2, 3). Gene expression signatures for PBZ on the 51 CMap platform showed appreciable similarity to classical histone deacetylase (HDAC) 52 inhibitors. An extensive comparison of PBZ with suberanilohydroxamic acid (SAHA) and 53 trichostatin A (TSA) demonstrated gene expression enrichment scores (connectivity) for PBZ 54 that compared equal to or greater than those for SAHA and TSA for several gene expression 55 signatures in MSigDB that are associated with histone modifications (1). 56 For example, this was true for gene expression signatures from ultraviolet exposure of the 57 epidermis in the 100 to 280 nm wavelength range (UVC class radiation); such exposures are 58 associated with trichothiodystrophy syndrome and xeroderma pigmentosum (4). PBZ also 59 showed highly similar gene expression signatures as those for the histone modifying effects of 60 SAHA and TSA on the viral replication process of human cytomegalovirus; these effects on 61 histones have a “therapeutic” value in the application of oncolytic cancer therapy that is herpes- 62 based (5-7). A third area of strong agreement among PBZ, SAHA and TSA related to the 63 similarities among their gene expression signatures to those resulting from ultraviolet radiation 64 of normal epidermal keratinocytes in the 280 to 320 nm range (UVB class radiation). This class 65 of radiation can result in the development of squamous cell or basal cell carcinoma. TSA has 3 bioRxiv preprint doi: https://doi.org/10.1101/767392; this version posted September 12, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 66 been demonstrated to aid in the recovery of markers of keratinocyte differentiation following 67 UVB radiation (8). A fourth area of overlap of gene enrichment scores among HDAC inhibitors 68 and PBZ related to the known inhibitory effects of TSA, SAHA, valproic acid and sodium 69 butyrate on colon cancer cell lines (9). 70 In vitro assays in the earlier work confirmed HDAC inhibitory activity for PBZ in several 71 classes of HDACs, with the greatest inhibition upon HDACs 5, 6 and 9(1). In the same 72 communication, inhibitory effects of PBZ were demonstrated on the proliferation of several 73 human tumor cell lines; the most sensitivity was observed in non-small-cell lung, lymphoma, 74 myeloma, ovarian, and prostate cell cultures. 75 The present study concerns further investigation of PBZ gene expression profiles in the new 76 cloud-based version of the Broad Institute gene expression database, the CLUE platform; this 77 database continues to be identified as the Connectivity Map (CMap) (10). However, the new 78 platform is a major expansion of the catalog of cellular gene signature responses of human 79 malignant and premalignant cells to chemical and genetic perturbation. 80 The analyses in the present study have identified a number of gene expression signatures for 81 PBZ that are closely similar to a large group of glucocorticoids, drugs that are known to have 82 anti-inflammatory and immunomodulatory actions; these agents have a steroid chemical 83 structure, but PBZ has no elements of such a structure (Fig 1). PBZ also had strong gene 84 signature connectivity with several groups of agents that have well-identified roles in the 85 inhibition of signaling pathways for malignant expansion. This appears to be supportive of the 86 previous observations of inhibition of growth in malignant tumor cell cultures 87 (1). The CLUE CMap also confirms the similarities among gene expression signatures for PBZ 88 and HDAC inhibitors in the expanded group of 9 malignant and premalignant cell lines. The 89 present studies of potential anti-proliferative, anti-inflammatory and immunomodulatory activity 4 bioRxiv preprint doi: https://doi.org/10.1101/767392; this version posted September 12, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 90 for PBZ would appear to support the previous observations and help to develop hypotheses for 91 repurposing PBZ for new therapeutic applications. Finally, recent studies by other investigators, 92 which are enumerated herein, are consistent with a broadening perspective about the potential 93 therapeutic attributes of the drug. 94 Fig 1. Chemical structure of phenoxybenzamine HCl 95 2. Methods 96 Both the earlier online Broad Institute CMap genomic dataset and the new cloud-based CLUE 97 platform are based on the gene expression signatures that result from the perturbation of actively 98 proliferating cells that are malignant and, in one case, premalignant. The database and 99 associated software are accessible at https://clue.io. The drugs, chemical agents and genetic 100 inputs are referred to as, “perturbagens” (2, 10). The present analyses focused on gene- 101 expression signatures located in the “TOUCHSTONE” dataset (accessed in the “Tools” menu) 102 that was selected because it represents a set of thoroughly annotated small molecule perturbagens 103 that would be expected to be relevant to comparisons with the possible effect of PBZ; see: 104 https://clue.io/connectopedia/tag/TOUCHSTONE. The Touchstone dataset contains a total of 105 approximately 8,400 perturbagens that have produced gene signatures that were generated from 106 testing on a panel of 9 cell lines; those cell lines are detailed in Table 1. In almost all instances, 107 the perturbagens were tested at a concentration of 10 µM, allowing for the comparison of the 108 strength of the connectivity of gene
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