1. Robert Ramer et al, 2012
University of Rostock, Germany
Presented by: Steven Addison

2. Major alkaloid found in cannabis
Used to treat epilepsy, spasms, anxiety, schizophrenia, nausea
Found to inhibit cancer growth (Mechoulam 2007)
Found to inhibit cancer cell invasiveness (McAllister 2007)
Tetrahydrocannabinol (THC) Methanandamide (MA)
Proliferation
Angiogenesis
Apoptosis
Autophagy

3. Decreases ID-1: Inhibitor of differentiation via H-L-H Transcription
Factors (McAllister 2007)
TIMP-1: Tissue inhibitor of matrix metalloproteinases, anti-invasive (Ramer 2010)
Signaling by CB1, CB2, TRPV1 (transient receptor potential vanilloid)
CBD, THC & MA (Ramer 2008)
ICAM-1: Intercellular adhesion molecule
Upregulated by CBD in lung cancer cells
?

4. Immunoglobulin superfamily
80-110 kDa transmembrane glycoprotein
Expressed on cell surfaces, binds β2 integrin
Trafficking inflammatory cells, immunosurveillance
Cell-cell interactions, antigen presentation
Signal transduction – MAPK (mitogen activated protein kinase)
Lymphocyte adhesion to tumor cells
Decreased metastasis of several cancer types
May upregulate TIMP-1
Klaus Ley 2001
Nature Medicine 7, 1105 - 1106

5. CBD and ICAM-1, TIMP-1 in cancer cells
Receptor involvement in CBD activity – CB1, CB2, TRPV1
ICAM-1 neutralizing antibody and CBD effects
ICAM-1 siRNA knockdown and CBD effects
Other cannabinoids – THC and MA
Primary metastasized human lung tumor cells
Metastasis study in vivo – athymic mice xenograft

6. Concentration-dependent
effect of CBD on ICAM-1
mRNA and protein
expression in A549 (A),
H358 (B), or H460 (C)
human cancer cell lines

7. Time course of ICAM-1 and TIMP-1 mRNA expression of CBD- or
vehicle-treated A549 (D), H358 (E), and H460 (F) cells assessed
by real-time RT-PCR

8. AM-251: CB1 antagonist
AM-630: CB2 antagonist
Capsazepine: TRPV1 antagonist
Effect of AM-251, AM-630, and capsazepine on CBD-induced
ICAM-1 protein expression and p42/44 MAPK activation.

9. SB203580: inhibitor of p38 MAPK activation
PD98059: inhibitor of p42/44 MAPK activation
Effect of SB203580 and PD98059 on CBD-induced ICAM-1
protein expression.

10. Effect of a neutralizing ICAM-1 antibody on anti-invasive and
TIMP-1-inducing action of CBD

11. Effect of ICAM-1 siRNA on anti-invasive and TIMP-1-inducing
action of CBD

12. Effect of THC and MA on
ICAM-1 mRNA expression.
Effect of an ICAM-1 antibody on TIMP-1
expression by THC and MA.

13. Influence of ICAM-1 siRNA on
the TIMP-1-inducing action of
THC and MA

14. Effect of the cannabinoids CBD, THC, and MA
on the invasiveness of primary tumor cells

15. Regulation of ICAM-1, TIMP-1, and
invasiveness by cannabinoids in
primary lung cancer cells

16. Role of ICAM-1 in CBD’s antimetastatic effect in athymic nude
mice xenografted with A549 cells and treated with CBD every
72 hours for 28 days

17. Cannabinoid role in anti-invasive TIMP-1 pathway elucidated
- receptor/MAPK mediated ICAM-1 upregulation discovered
ICAM-1 shown to be a key player in anti-invasive mechanism
Anticarcinogenic properties of cannabinoids demonstrated in
metastasized primary tumor cells from humans
In vivo demonstration of an inhibitor-based antimetastatic
mechanism elicited by cannabinoids

18. CLINICAL TRIALS