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Endorphins are an endogenous morphine neuropeptides
produced from pituitary gland in response to stress and pain. There are three
types of endorphins beta-endorphins, enkephalins and dynorphins binds to mu
(µ), kappa (ĸ) and delta (ɗ) receptors situated on nervous system and immune
cells. Beta endorphin is an abundant endorphin synthesized and stored in the
anterior pituitary gland. It has got various activities such as immune
stimulatory, anti-inflammatory, analgesic, anti-aging, stress buster activity involved
in holistic preventive, promotive, therapeutic and palliative treatment of
inflammation associated cancer without adverse effects. This article briefs
about the recent basic research findings of beta endorphins. A novel holistic
preventive, therapeutic, health promotive and palliative treatment of cancer.
Keywords: Cortisol,
Noradrenaline, ACTH, IL-1β, IL-6, TNF-α, COX-2, NF-KB, STAT-3
INTRODUCTION
Cancer is a major threat to mankind. Majority
of cancers more than 90% of all cancers are due to external environmental
factors such as tobacco, alcohol, chemical ingestion such as arsenic, silica,
bismuth, lead and benzene. One of a cause for cancer is human environment that
is human mind is a part of consciousness. Chronic inflammation is considered as
a seventh hallmark of cancer. Chronic infection or chronic inflammation
accounts 25% of all cancer. Chronic inflammatory conditions or injury that are
associated with malignancy are Lichen planus, Oral submucous fibrosis, chronic
periodontitis associated oral squamous cell carcinoma, sialadenitis related
salivary gland carcinoma, Gastric acid associated Barrett’s metaplasia and
reflux esophagitis associated esophageal carcinoma, Sjogren’s syndrome and
Hashimoto’s thyroiditis associated mucosa associated lymphoid tissue lymphoma,
UV radiation associated skin inflammation mediated malignant melanoma. Silica,
asbestosis, smoking associated silicosis and bronchitis associated lung
carcinoma, Prostatitis induced prostate carcinoma, chronic pancreatitis induced
pancreatic cancer, Hepatitis B induced hepatocellular carcinoma and HPV induced
cervical cancer and pharyngeal cancer. Human herpes virus 8 (HHV8) induced
Kaposi’s sarcoma [3].
Advanced cancer treatment modalities such as
surgery, chemotherapy and radiotherapy fails to improve the prognosis of cancer
with increasing morbidity, mortality, adverse drug reactions and decreasing
survival rate [10-17].
I do not know any treatment, which can kill
cancer cells without killing normal cells. Normal cells and cancer cells work
alike (Albert Zen gyorgi) [18-20].
Beta-endorphins are abundant endorphins, more
potent than morphine, synthesized and stored in the anterior pituitary gland;
it is a precursor of POMC (Proopimelanocortin) [21-26].
Most of all immune cells produce endorphins.
In inflammatory state recruitment of immune cells to the site of
Endorphins produced during yoga, intense
physical exercise creates a psychological relaxed state known as “Runner’s
High”, mindful meditation, pranic healing, pranayama, chi therapy, acupuncture,
music therapy, tender, love, care, sympathy, empathy in caring the patient
[31-33].
Mechanism of action
of beta endorphins in anticancer activity
Chronic psychological stress induced release
of CRH from hypothalamus activates HPA-axis through ANS release neuropeptides
such as cortisol, noradrenaline and ACTH activates IL-1β, TNF-α, IL-6 and
COX-2, inflammatory mediators, which activates NF-KB,STAT-3 transcription
factors involved in chronic inflammation and cancer by induced expression of
inflammatory mediators such as (BCL-2, BCL-XL, survivin, IAP1/2) involved in
cell survival (MHC-1, MHC-11, cytokines) involved in chronic inflammation
(IL-8, VEGF, COX-2) involved in angiogenesis (Cyclin D, C-Myc, P21) involved in
cell proliferation (ICAM-1, VCAM-1, ELAM-1, UPA, fibronectin, E-selectin,
Mmp-2,9, CXCR4) involved in invasion and metastasis [1-7,29,31-33].
In the peripheral nervous system (PNS)
binding of beta-endorphins to the µ (mu) receptors on peripheral nerves results
in inhibition of substance P a neurotransmitter of pain and inflammation,
produce IL-10, IL-18 and IFN-ϒ anti-inflammatory cytokines [31-34].
In the central nervous system (CNS) binding
of beta endorphins to the µ (mu) receptors on central nervous system instead of
inhibiting substance p, it inhibits GABA (Gama amino butyric acid) inhibitory
neurotransmitter, activates dopamine neurotransmitter involved in analgesic
activity, euphoria, tranquillity of mind, self-reward, cognitive development
and stress buster activity [31-34].
Endorphin receptors are situated on immune
cells. Binding of beta endorphins to the
µ (mu) receptors on immune cells such as NK cells, DC’s, neutrophils,
macrophages, T cells and B cells results in activation and release of opsonin, granzyme-B and IFN-Ƴ
involved in antibacterial, antiviral, antitumor and anti-inflammatory activity
[31-33].
Beta-endorphins inhibits chronic
psychological stress induced sympathetic nervous system activity and activates
parasympathetic nervous system activity of ANS (Autonomic nervous system)
mediated inhibition of release of neuropeptides such as cortisol, ACTH,
noradrenaline, through HPA-axis results in inhibition of inflammatory mediators such as IL-1β, TNF-α,
IL-6 and COX-2, which activates NF-KB, STAT-3 transcription factors involved in
chronic inflammation and cancer [8-14].
Beta-endorphins inhibits chronic
psychological stress induced activation of NF-KB transcription factor involved
in tumour progression, which antagonize the P53 tumour suppressor gene, a
guardian of the genome mutated in more than 50% of all cancers by inflammatory
mediators such as NO (nitric oxide), ROS, RNS free radicals, AID (Activated
induced cytidine deaminase) enzyme [31-33].
Beta-endorphins express epithelial E-Cadherin
involved in epithelial cell attachment, loss of epithelial E-cadherin involved
in EMT (epithelial mesenchymal transition) induced tumor invasion.
Beta endorphins involved in reduction of cell
proliferation, apoptotic activity by activating NK cells mediated release of
apoptotic proteins such as granzyme A and B, perforins and FASL
[15-20,29,31-33].
Beta-endorphins delay aging by lengthening
telomeres, which otherwise shorten with aging and other mechanism is by
inhibiting free radicals (ROS, RNS) release during oxidative stress via NADPH
oxidase pathway produced by inflammatory cells such as neutrophils, macrophages
and dendritic cells involved in cell aging, genetic mutation, tissue damage and
cell death [21-28,31-33].
Beta endorphins inhibits NF-KB a key
transcription factor involved in conversion of TH1 lymphocytic type to TH2
lymphocytic type release IL-4, IL-13, along with TH17 cells facilitate chronic
inflammation, immune modulation and tissue damage, altered induced Tregs
(Regulatory T cells) formed from TH1 cells mediated by TGF-β inflammatory
mediator release IL-10, IL-2, IL-17, IL-4, IL-13, IL-5 involved in immune
modulation, otherwise normally involved in self-tolerance and immune
homeostasis, growth factors such as (EGF, FGF, VEGF) involved in cell
proliferation and angiogenesis, mmp’s 2,9 (matrix metalloproteases 2,9)
involved in extracellular matrix degradation, tumor invasion and metastasis
[29-34].
CONCLUSION AND FUTURE
PERSPECTIVE
Beta-endorphins are an endogenous morphine
acts as a holistic preventive, therapeutic, health promotive and palliative
treatment of cancer by its analgesic, anti-inflammatory, immune stimulatory and
stress buster activity without adverse effects and inexpensive. Thorough
understanding of endorphins, activities that produce endorphins, mechanism of
action, dose dependent duration of action, prognosis related to disease helpful
for future therapeutic applications in treatment of cancer.
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