Broad targeting of angiogenesis for cancer prevention and therapy

Semin Cancer Biol. 2015 Dec;35 Suppl:S224-S243. doi: 10.1016/j.semcancer.2015.01.001. Epub  2015 Jan 16.
Broad targeting of angiogenesis for cancer prevention and therapy.
Wang Z1, Dabrosin C2, Yin X3, Fuster MM3, Arreola A4, Rathmell WK4, Generali D5, Nagaraju GP6, El-Rayes B6, Ribatti D7, Chen YC8, Honoki K9, Fujii H9, Georgakilas AG10, Nowsheen S11, Amedei A12, Niccolai E12, Amin A13, Ashraf SS14, Helferich B15, Yang X15, Guha G16, Bhakta D16, Ciriolo MR17, Aquilano K17, Chen S18, Halicka D19, Mohammed SI20, Azmi AS21, Bilsland A22, Keith WN22, Jensen LD23.

Author information                                                       Free PMC Article

Abstract

Deregulation of angiogenesis–the growth of new blood vessels from an existing vasculature–is a main driving force in many severe human diseases including cancer. As such, tumor angiogenesis is important for delivering oxygen and nutrients to growing tumors, and therefore considered an essential pathologic feature of cancer, while also playing a key role in enabling other aspects of tumor pathology such as metabolic deregulation and tumor dissemination/metastasis. Recently, inhibition of tumor angiogenesis has become a clinical anti-cancer strategy in line with chemotherapy, radiotherapy and surgery, which underscore the critical importance of the angiogenic switch during early tumor development. Unfortunately the clinically approved anti-angiogenic drugs in use today are only effective in a subset of the patients, and many who initially respond develop resistance over time. Also, some of the anti-angiogenic drugs are toxic and it would be of great importance to identify alternative compounds, which could overcome these drawbacks and limitations of the currently available therapy. Finding “the most important target” may, however, prove a very challenging approach as the tumor environment is highly diverse, consisting of many different cell types, all of which may contribute to tumor angiogenesis. Furthermore, the tumor cells themselves are genetically unstable, leading to a progressive increase in the number of different angiogenic factors produced as the cancer progresses to advanced stages. As an alternative approach to targeted therapy, options to broadly interfere with angiogenic signals by a mixture of non-toxic natural compound with pleiotropic actions were viewed by this team as an opportunity to develop a complementary anti-angiogenesis treatment option. As a part of the “Halifax Project” within the “Getting to know cancer” framework, we have here, based on a thorough review of the literature, identified 10 important aspects of tumor angiogenesis and the pathological tumor vasculature which would be well suited as targets for anti-angiogenic therapy: (1) endothelial cell migration/tip cell formation, (2) structural abnormalities of tumor vessels, (3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluid pressure, (6) poor perfusion, (7) disrupted circadian rhythms, (8) tumor promoting inflammation, (9) tumor promoting fibroblasts and (10) tumor cell metabolism/acidosis. Following this analysis, we scrutinized the available literature on broadly acting anti-angiogenic natural products, with a focus on finding qualitative information on phytochemicals which could inhibit these targets and came up with 10 prototypical phytochemical compounds: (1) oleanolic acid, (2) tripterine, (3) silibinin, (4) curcumin, (5) epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9) withaferin A and (10) resveratrol. We suggest that these plant-derived compounds could be combined to constitute a broader acting and more effective inhibitory cocktail at doses that would not be likely to cause excessive toxicity. All the targets and phytochemical approaches were further cross-validated against their effects on other essential tumorigenic pathways (based on the “hallmarks” of cancer) in order to discover possible synergies or potentially harmful interactions, and were found to generally also have positive involvement in/effects on these other aspects of tumor biology. The aim is that this discussion could lead to the selection of combinations of such anti-angiogenic compounds which could be used in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reduced toxicity and circumvention of single-agent anti-angiogenic resistance, as well as for possible use in primary or secondary cancer prevention strategies.
Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

KEYWORDS:
Angiogenesis; Anti-angiogenic; Cancer; Phytochemicals; Treatment

PMID:   25600295
Free PMC Article

PMCID:   PMC4737670

Drug that helps addicts may help treat cancer too, say experts

Date:

June 27, 2016

Source:

University of St George’s London

Summary:

The drug naltrexone (LDN), which is used to treat addicts, can have a beneficial impact on cancer patients if it is given in low doses, new research suggests. 

Scientists at St George’s, University of London, say the drug naltrexone (LDN), which is used to treat addicts, can have a beneficial impact on cancer patients if it is given in low doses.

Researchers discovered that not only does LDN cause cancer cells to stop growing, it also alters their internal machinery, making them more likely to kill themselves. This can lead to other treatments becoming more effective.

The research team, led by Dr Wai Liu and Professor Angus Dalgleish and working with the company LDN Pharma, discovered that the drug, when used in these small doses, can alter the genes that regulate how a cancer cell behaves. LDN can reactivate genes that promote cell killing, as well as modify the genes that interact with the immune system to make it more unfriendly to cancer.

Dr Liu said: “We have shown that the genetic fingerprint of naltrexone differs according to the different doses used, which identifies new ways of using it as an anti-cancer treatment.

“Rather than stopping the cancer cells from growing, patients want to be rid of them. We saw that by giving the drug for two days, then withdrawing it, cancer cells would stop cycling and undergo cell death.”

Dr Liu, who has spent 20 years researching cancer treatment, hopes his research will prompt clinical trials for the use of LDN on cancer patients. He foresees LDN being used in conjunction with other cancer treatments.

At present naltrexone is licensed in many countries for the treatment of alcohol and heroin addiction, but the doses used is much higher than in this study.

However, it isn’t licensed for the treatment of other illnesses, and patients are obtaining it ‘off label’ to treat conditions such as multiple sclerosis and fibromyalgia.

Dr Liu added: “We have taken a drug that is relatively safe in humans, and reformulated a new use for it; this has only been possible by understanding the dynamics of a drug. How many other drugs can be improved in this way?

“We have shown a similar ‘repackaging’ benefit with the antimalarial drug artesunate and the cannabinoids. In both cases, drugs that are not classically cancer therapies are being trialled as such.

“This helps clinicians to devise new ways to tackle a disease that affects so many.”

The research has been published in the International Journal of Oncology.

---

Story Source:

The above post is reprinted from materials provided by University of St George’s London. Note: Materials may be edited for content and length.

---

Journal Reference:

1. Wai Liu, Katherine Scott, Jayne Dennis, Elwira Kaminska, Alan Levett, Angus Dalgleish. Naltrexone at low doses upregulates a unique gene expression not seen with normal doses: Implications for its use in cancer therapy. International Journal of Oncology, 2016; DOI: 10.3892/ijo.2016.3567

 

Broad targeting of angiogenesis for cancer prevention and therapy.

SeminCancer Biol.2015 Jan 16. pii: S1044-579X(15)00002-4. doi: 10.1016/j.semcancer.2015.01.001.[Epub ahead of print]
Broad targeting ofangiogenesis for cancer prevention and therapy.
Wang Z1, Dabrosin C2, Yin X3, Fuster MM3, Arreola A4, Rathmell WK4, Generali D5, Nagaraju GP6, El-Rayes B6, Ribatti D7, Chen YC8, Honoki K9, Fujii H9, Georgakilas AG10, Nowsheen S11, Amedei A12, Niccolai E12, Amin A13, Ashraf SS14, Helferich B15, Yang X15, Guha G16, Bhakta D16, Ciriolo MR17, Aquilano K17, Chen S18, Halicka D19, Mohammed SI20, Azmi AS21, Bilsland A22, Keith WN22, Jensen LD23.
Author information

1Department of Urology, Massachusetts General Hospital,     Harvard Medical School, Boston, MA, USA. Electronic address:     zwang0@partners.org.

2Department of Oncology, Linköping University,     Linköping, Sweden; Department of Clinical and Experimental Medicine,     Linköping University, Linköping, Sweden.

3Medicine and Research Services, Veterans Affairs San     Diego Healthcare System & University of California, San Diego, San     Diego, CA, USA.

4Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC,     USA.

5Molecular Therapy and Pharmacogenomics Unit, AO Isituti     Ospitalieri di Cremona, Cremona, Italy.

6Department of Hematology and Medical Oncology, Emory     University, Atlanta, GA, USA.

7Department of Basic Medical Sciences, Neurosciences and     Sensory Organs, University of Bari Medical School, Bari, Italy; National Cancer Institute Giovanni Paolo II, Bari, Italy.

8Department of Biology, Alderson Broaddus University,     Philippi, WV, USA.

9Department of Orthopedic Surgery, Arthroplasty and     Regenerative Medicine, Nara Medical University, Nara, Japan.

10Physics Department, School of Applied Mathematics and     Physical Sciences, National Technical University of Athens, Athens,     Greece.

11Mayo Graduate School, Mayo Clinic College of Medicine,     Rochester, MN, USA.

12Department of Experimental and Clinical Medicine,     University of Florence, Florence, Italy.

13Department of Biology, College of Science, United Arab     Emirate University, United Arab Emirates; Faculty of Science, Cairo     University, Cairo, Egypt.

14Department of Chemistry, College of Science, United     Arab Emirate University, United Arab Emirates.

15University of Illinois at Urbana Champaign, Urbana, IL,     USA.

16School of Chemical and Bio Technology, SASTRA     University, Thanjavur, India.

17Department of Biology, University of Rome “Tor     Vergata”, Rome, Italy.

18Ovarian and Prostate Cancer Research Trust Laboratory, Guilford, Surrey, UK.

19New York Medical College, New York City, NY, USA.

20Department of Comparative Pathobiology, Purdue     University Center for Cancer Research, West Lafayette, IN, USA.

21School of Medicine, Wayne State University, Detroit,     MI, USA.

22Institute of Cancer Sciences,     University of Glasgow, Glasgow, UK.

23Department of Medical, and Health Sciences, Linköping     University, Linköping, Sweden; Department of Microbiology, Tumor and Cell     Biology, Karolinska Institutet, Stockholm, Sweden. Electronic address:     lasse.jensen@liu.se.

Abstract
Deregulation of angiogenesis – the growth of new blood vessels from an existing vasculature -is a main driving force in many severe human diseases including cancer.As such, tumor angiogenesis is important for delivering oxygen and nutrients togrowing tumors, and therefore considered an essential pathologic feature of cancer, while also playing a key role in enabling other aspects of tumor pathology suchas metabolic deregulation and tumor dissemination/metastasis. Recently,inhibition of tumor angiogenesis has become a clinical anti-cancerstrategy in line with chemotherapy, radiotherapy and surgery,which underscore the critical importance of the angiogenic switch during earlytumor development. Unfortunately the clinically approved anti-angiogenic drugsin use today are only effective in a subset of the patients, and many whoinitially respond develop resistance over time. Also, some of theanti-angiogenic drugs are toxic and it would be of great importance to identifyalternative compounds, which could overcome these drawbacks and limitations ofthe currently available therapy. Finding “the most important target”may, however, prove a very challenging approach as the tumor environment ishighly diverse, consisting of many different cell types, all of which may contribute to tumor angiogenesis. Furthermore, the tumor cells themselves are genetically unstable, leading to a progressive increase in the number of different angiogenic factors produced as the cancer progresses to advanced stages. Asan alternative approach to targeted therapy, options to broadly interfere withangiogenic signals by a mixture of non-toxic natural compound with pleiotropicactions were viewed by this team as an opportunity to develop a complementaryanti-angiogenesis treatment option. As a part of the “HalifaxProject” within the “Getting to know cancer” framework, we have here,based on a thorough review of the literature, identified 10 important aspectsof tumor angiogenesis and the pathological tumor vasculature which would bewell suited as targets for anti-angiogenic therapy: (1) endothelial cellmigration/tip cell formation, (2) structural abnormalities of tumor vessels,(3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluid pressure,(6) poor perfusion, (7) disrupted circadian rhythms, (8) tumor promotinginflammation, (9) tumor promoting fibroblasts and (10) tumor cellmetabolism/acidosis. Following this analysis, we scrutinized the availableliterature on broadly acting anti-angiogenic natural products, with a focus onfinding qualitative information on phytochemicals which could inhibit thesetargets and came up with 10 prototypical phytochemical compounds: (1) oleicacid, (2) tripterine, (3) silibinin, (4) curcumin, (5)epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9)withaferin A and (10) resveratrol. We suggest that these plant-derived compounds could becombined to constitute a broader acting and more effective inhibitory cocktailat doses that would not be likely to cause excessive toxicity. All the targetsand phytochemical approaches were further cross-validated against their effectson other essential tumorigenic pathways (based on the “hallmarks” of cancer) in order to discover possible synergies or potentially harmful interactions,and were found to generally also have positive involvement in/effects on theseother aspects of tumor biology. The aim is that this discussion could lead tothe selection of combinations of such anti-angiogenic compounds which could beused in potent anti-tumor cocktails, for enhanced therapeutic efficacy, reducedtoxicity and circumvention of single-agent anti-angiogenic resistance, as well as for possible use in primary or secondary cancer prevention strategies.
Copyright ©2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

PMID:
25600295
[PubMed – as supplied by publisher]
Free full text

10 Prototypical Phytochemical Compounds to Treat and Prevent Cancer

I’m reposting this because I think that this is an important article. The full article is

available for free at pubmed.gov   (see attachment if it posts on the list serve)

It’s authored by 32 members of an international cancer research group,

working as part of the “Halifax Project”.

They came up with 10 prototypical phytochemical compounds to both treat and

prevent cancer. Five of the ten are already in my cocktail: silibinin (milk thistle),

epigallocatechin-gallate (green tea), curcumin, melatonin and resveratrol.

I’m currently looking up sources for the other compounds…

oleic acid is found in     olive oil,

tripterine is found in a Chinese herb (thunder god vine),

kaempferol is     found     in canned capers

enterlactone      7-HMR lignans   SWU334  60  40mg caps  $ 14.99 (swanson’s)

withaferin A  is found in the Chinese  (winter cherry)

Bill

Deregulation ofangiogenesis – the growth of new blood vessels from an existing vasculature -is a main driving force in many severe human diseases including cancer. Assuch, tumor angiogenesis is important for delivering oxygen and nutrients togrowing tumors, and therefore considered an essential pathologic feature ofcancer, while also playing a key role in enabling other aspects of tumorpathology such as metabolic deregulation and tumor dissemination/metastasis.Recently, inhibition of tumor angiogenesis has become a clinical anti-cancerstrategy in line with chemotherapy, radiotherapy and surgery, which underscorethe critical importance of the angiogenic switch during early tumordevelopment. Unfortunately the clinically approved anti-angiogenic drugs in usetoday are only effective in a subset of the patients, and many who initiallyrespond develop resistance over time. Also, some of the anti-angiogenic drugsare toxic and it would be of great importance to identify alternativecompounds, which could overcome these drawbacks and limitations of thecurrently available therapy. Finding “the most important target” may,however, prove a very challenging approach as the tumor environment is highlydiverse, consisting of many different cell types, all of which may contributeto tumor angiogenesis. Furthermore, the tumor cells themselves are geneticallyunstable, leading to a progressive increase in the number of differentangiogenic factors produced as the cancer progresses to advanced stages. As analternative approach to targeted therapy, options to broadly interfere withangiogenic signals by a mixture of non-toxic natural compound with pleiotropicactions were viewed by this team as an opportunity to develop a complementaryanti-angiogenesis treatment option. As a part of the “HalifaxProject” within the “Getting to know cancer” framework, we havehere, based on a thorough review of the literature, identified 10 importantaspects of tumor angiogenesis and the pathological tumor vasculature whichwould be well suited as targets for anti-angiogenic therapy: (1) endothelialcell migration/tip cell formation, (2) structural abnormalities of tumorvessels, (3) hypoxia, (4) lymphangiogenesis, (5) elevated interstitial fluidpressure, (6) poor perfusion, (7) disrupted circadian rhythms, (8) tumorpromoting inflammation, (9) tumor promoting fibroblasts and (10) tumor cellmetabolism/acidosis. Following this analysis, we scrutinized the availableliterature on broadly acting anti-angiogenic natural products, with a focus onfinding qualitative information on phytochemicals which could inhibit thesetargets and came up with 10 prototypical phytochemical compounds: (1) oleicacid, (2) tripterine, (3) silibinin, (4) curcumin, (5)epigallocatechin-gallate, (6) kaempferol, (7) melatonin, (8) enterolactone, (9)withaferin A and (10) resveratrol. We suggest that these plant-derivedcompounds could be combined to constitute a broader acting and more effectiveinhibitory cocktail at doses that would not be likely to cause excessivetoxicity. All the targets and phytochemical approaches were furthercross-validated against their effects on other essential tumorigenic pathways(based on the “hallmarks” of cancer) in order to discover possiblesynergies or potentially harmful interactions, and were found to generally alsohave positive involvement in/effects on these other aspects of tumor biology.The aim is that this discussion could lead to the selection of combinations ofsuch anti-angiogenic compounds which could be used in potent anti-tumorcocktails, for enhanced therapeutic efficacy, reduced toxicity andcircumvention of single-agent anti-angiogenic resistance, as well as forpossible use in primary or secondary cancer prevention strategies.

Copyright ©2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

KEYWORDS:

PMID: 25600295

[PubMed – as supplied by publisher]

Free full text