Cancer Initiation: Solving the mystery of Low Dose Naltrexone (LDN) and Cancer treatment

Wednesday, January 11, 2017

Solving the mystery of Low Dose Naltrexone (LDN) and Cancer treatment

 Naltrexone was developed as an opioid receptor antagonist, that is, it blocks the opioid receptor and was seen as an alternative to methadone for the treatment of opium addiction. The mystery then is "Why is this drug  useful for the treatment of ovarian and potentially other forms of cancer?". First we must talk a little bit about the cell cycle, and what determines if a colony of cells will remain in the cell cycle, that is actively dividing, as is the case in cancer.
  The first reason that cell division may be continually active is that the gene and protein product for retinoblastoma ( the protein is pRB) is inactive.
  In brief summary, as a cell matures through the various phases of the cell cycle, G1, S, G2 and Mitosis( M ), it produces proteins called "cyclins". The purpose of these cyclins is to activate "Cyclin Dependent Kinases". A Kinase is an enzyme that adds a phosphate group to a substrate. In
 the case of CDK, the substrate is pRB, ( retinoblastoma ). When pRB becomes phosphorylated by CDK's it is unable to bind to E2F. E2F is a transcription factor that can move to the nucleus of the cell and bind to promoters on the DNA of the cell. When promoters are bound by a transcription factor such as E2F, they are activated and begin to produce messenger RNA, ( transcription ) and subsequently proteins ( translation ) .
  So then we see that when pRB is not present, E2F is always unbound and the cell remains constuitively in the cell cycle. But cancer cells can be locked in the cell for other reasons. In the case of ovarian cancer cells, the cells are very often inappropriately responding to hormones such as estrogen. In this case, pRB may be functional.
 There are pathways that are known to inhibit progression through the cell cycle. These include pathways that activate p16 or p21. These proteins have the ability to block cell cycle regulation at the cyclin dependent kinase (CDK) level.
    So then we see that if we had a way to activate the p16 or p21 pathways in cancer cells where pRB was functional, we would have a way to stop the cancer cells.

  Next, we note that the  opioid growth factor receptor ( OGRr ) is active on ovarian cancer cells. This means that these cells react to both naltrexone and natural opioids. This pathway is INHIBITIVE of cell growth and progression through the cycle!
 
This is what Donahue et. al. is describing in reference [1].

 The mechanism of OGF-OGFr action on DNA synthesis was related to the cyclin-dependent kinase inhibitory pathway because knockdown of p16 or p21 in OVCAR-3 cells, and p21 in SKOV-3 cells, eliminated OGF's inhibitory effect on growth. These data are the first to report that the OGF-OGFr system is a native biological regulator of cell proliferation in human ovarian cancer [1]
The term "knockdown of p16 and p21" here means that in laboratory experiments, expression of these proteins was blocked, and when this was done, the inhibitory affect of stimulation of the OGFr was eliminated.

In conclusion we note the important findings that:
  •  pRB is intact in many types of ovarian cancer, they are being forced through the cell cycle by receptors for other growth factors. 
  • the opioid growth factor receptor OGFr is active in ovarian cancer cells and stimulates cyclin dependendent kinase inhibitory pathways mediated by p16 and p21.
  • stimulation of the OGFr by naltrexone ( low dose naltrexone,  LDN ) arrests the cell cycle in many ovarian cancer cells.
  • As such there is a new approach to the treatment of cancer based upon the specific molecular characterization of these cells.
  • Molecular diagnostic techniques continue to become increasingly important in the evaluation and treatment of ovarian and many other types of cancer. [2]
  • In the case cancer types other than ovarian, it would be helpful to determine if the particular cancer biopsy is positive for the OGFr, and pRB to predict if it also might be responsive to LDN.
References 

[1] Donahue RN1, McLaughlin PJ, Zagon IS. Cell proliferation of human ovarian cancer is regulated by the opioid growth factor-opioid growth factor receptor axis. Am J Physiol Regul Integr Comp Physiol. 2009 Jun;296(6):R1716-25. Epub 2009 Mar 18. [Full Text]

[2] Ian S Zagon, Renee Donahue, Patricia J McLaughlin,  Targeting the opioid growth factor: Opioid growth factor receptor axis for treatment of human ovarian cancer, Experimental Biology and Medicine, Volume 238, Issue 5, 2013 ( Full Text )

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