Omega fatty acids and cancer therapy PowerPoint Presentation by mikeholy

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									Omega-3 fatty acids and cancer therapy

           W. Elaine Hardman, Ph.D.
   Department of Biochemistry and Microbiology
     Marshall University School of Medicine
            Huntington, West Virginia
Outline
•What are omega 3 fatty acids?

•Pre-clinical evidence for benefit of n-3 fatty acids during cancer
therapy

• Potential mechanisms for therapeutic benefit of n-3 fatty acids

• Clinical evidence for benefit of n-3 fatty acids during cancer
therapy
                 Major fat types
Saturated fat                                      O
                 17 15 13 11       9   7   5   3   C    OH
  Stearic
   18:0


Monounsaturated fat
                                               O
         18 16        12       9
 Oleic                                         C       OH
 (OA)
 18:1n-9
Polyunsaturated fats
                                       O
                         13   12   9   C
Linoleic                                   OH
 (LA)
18:2n-6        18



                                       O
Linolenic 18        15        12   9   C   OH
 (LNA)
 18:3n-3
 Pre-clinical evidence for benefit of omega-3 fatty
            acids during cancer therapy




Supplementing the diet with omega-3 fatty acids may
suppress the growth of existing cancers and may prevent or
slow metastasis

Omega 3 fatty acids may increase the efficacy of chemo- or
radiation therapy
Hormone responsive tumors such as:
          breast, prostate and colon cancers
seem especially sensitive to omega 3 fatty acids.


However, in animal models, lung cancer growth has
been also slowed by omega 3 fatty acids.
                          MDA-MB 231 growth after initiation of DOX
                        900
Mean tumor size (mm )
3                       800                                    Corn oil diet
                        700
                        600
                        500
                        400
                        300
                        200
                                                                Omega 3 diet
                        100
                          0
                              0   5   10   15   20   25   30      35
                            Number days after initiation of DOX
                                Growth rate mm3/day  SEM
                          CO    24.2  1.1               N-3        5.1  0.4
                          COdox  3.3  0.6               N-3dox    -0.1 
                                  Growth of A549 lung cancer xenografts in nude mice

                        750                       Beginning of DOX and ferric citrate
                                                                                           Diet
Mean tumor size (mm )
3




                                                                                          20% Corn oil (no DOX treatment)

                        500

                                                                                          19 % Fish oil
                                                                                          19% Fish oil and ferric citrate
                        250                                                               20% Corn oil


                                            Phase I     Phase II time of treatment
                          0
                              0              10               20                     30
                                    Days after initiation of fish oil diet
                        75
                                    MCF7 Tumors
Mean tumor size (mm3)



                        50
                                                    Control, no CPT-11
                        25
                         0
                                5       10     15      20
                        -25                         Corn oil, CPT-11
                        -50                         3% Fish oil, CPT-11
                                                    6% Fish oil, CPT-11
                        -75
                              Days after start of CPT-11
In animal models, the efficacies of:
       epirubicin (Bougnoux),
       5-fluorouracil (Hochwald),
       mitomycin C (Pardini),
       araC (Cha) and
       tamoxifen (DeGraffenried)
have also been enhanced in the presence of an omega 3 dietary
supplement.
Omega 3 fat may increase radiation sensitivity
              of cancer cells
Irradiation reduced the size of chemically induced rat
mammary gland tumors (Colas, et al).

               Percent decrease in size of
              tumor 12 days after radiation
         60

         50

         40

         30

         20

         10

          0
                   Control      DHA fed
Metaphase index in MDA-231 tumors of mice fed omega 6
or omega 3 diets with or without gamma irradiation
                                  a
                        1.5                       a,b
      Metaphase index




                        1.0
                                                          b,c

                        0.5                                                      c


                        0.0
                              O




                                                           3




                                                                                 d
                                                 d




                                                        n-




                                                                              ra
                                              ra
                              C




                                                                           st
                                             st




                                                                         po
                                           po




                                                                         s
                                          s




                                                                      hr
                                       hr




                                                                  24
                                      24




                                                                  3
                                   O




                                                               n-
                                  C
Omega 3 fatty acids may reduce cancer cachexia



   Cachexia – from Greek kachexia - bad condition

       General physical wasting and malnutrition

 Usually associated with increasing tumor mass. Cannot
         be corrected by increasing food intake
     Cancer cachexia




Omega 3            Omega 6
Potential mechanisms for therapeutic benefit
                     Model for Actions of n-3 PUFA in cells
       Oxidative Stress
LPS, irradiation, UV, Fe and other
prooxidants or chemotherapeutic drugs                      Vit E




                                       ids e:
                          PA




                                    Lip mag
                      or E                                 Damage:
                   AA                                      Proteins




                                     Da
                                                           DNA                                               Fish oil
                          ROS                                         activate




                                                                                                    EP
                                                           PO4




                                                                                                      A
                                                                                                                  Corn oil




                                                                                                 PL

                                                                                                    or
   A




                                                       IB-P          I BNF B




                                                                                                   A2

                                                                                                       A
EP




                                                                                      EPA




                                                                                                             A
                                                                                                         or
                                                                                                            PL
                                                                                                    AA




                                                                                                              C
   n-3 PUFA                                                                                                      Vit. E
        8-HETE                                                         NFB        COX2
     WY-14,649                                                                       or            NSAIDS
      cloxibrate                                                                    LOX
   some NSAIDS              PPAR cis retinol receptor                                    if from TBX2 enhances platelet aggregation
        DHEAS                                                                             AA        LTB4 proinflammatory
                                                                                                    PGE2 proproliferative
                                                                                      if from
                                                                                      EPA           PGE3 antiinflammatory
                                                                                                    LTB5 antiproliferative
                                                                                   IL-1             TBX3 retards platelet aggregation
                     Peroxisome                 PPREs NFB - REs induce
                                                genes     genes                    IL-6
                      -oxidation                                                              proliferation
                                                                                   IL-12 inflammation
                                                    Nucleus
           lipid binding proteins                                                  MMIF
                 P450 isozymes
                         AOEs                                                      TNF




                                                                                          COX - cyclooxygenase
                                                                                          LOX - lipoxygenase
      Free radicals
                   -
Superoxide        O2
                      
Hydroxyl         HO
                          
Hydroperoxyl     HO2

Hydrogen peroxide         H2O2
Lipid peroxide            LO2H


Reactive nitrogen species
Thiyl
                                 Membranes


                                 Mitochondria


                                 Enzymes


                                 Chromosomes
                                 DNA




Scientific American, Dec. 1992
Defenses from oxidative damage

Endogenous antioxidative enzymes:
      Superoxide dismutase
      Catalase
      Glutathione peroxidase

Exogenous antioxidants:
      Vitamin E and beta carotenes
      Uric acid and Vitamin C
      Metal chelators
How could the efficacy of chemotherapy be altered
without causing additional damage to normal cells?

  1. Most chemotherapeutic drugs cause oxidative
     damage to cells.

  2. Fat composition of all tissues can be altered by
     changing the fats content of the diet.

  3. Activity of endogenous antioxidative enzymes can be
     altered in cells.
A higher activity of SOD and lower activity of GPX would result in the
accumulation of H2O2. If catalase is not increased, accumulated H 2O2
could react with Fe2 to yield highly reactive OH · and · + Fe 3.
                                                       OH

                            GSH          2GSH              GSSG
    Product of
                       ·-
                      O2
    respiratory                               H2O2           2H20
                                  SOD                GPX
    chain
                                        Fe2          ·OH + OH · + Fe3
                                                                                                 Superoxide dismutase

                                                            20                                      50                    15




                                     (mean  SEM units/mg
                                                                     B   B                          40
                                                                                                                          10




                                           protein)
                                                                                                    30
                                                            10
                                                                                                    20




                                                                                   No specimen
                                                                                                                           5
                                                                 A
                                                                                                    10


  Antioxidant enzyme                                        0                                        0                     0


                                                                                                     Catalase
 activity in mice fed 5%                                    30
                                                                                                    150           A   A   7.5




                              (mean  SEM mmol H 2O2
CO or 3% FOC/2% CO




                                decomposed/min/mg
                                                            20                                      100                   5.0




                                      protein)
  diets with or without                                                                                   B
                                                                                                              B




                                                                             No specimen
                                                            10                                      50                    2.5

DOX treatment for 2 wks                                      0                                       0                    0.0


                                                                              Glutathione peroxidase
                           (mean  SEM mol           750                                          1000               A   100
                           b-NADP oxidized/g
                                protein)                                                            750                   75
                                                      500                                                         A
                                                                                                    500                   50
                                                                                                              B




                                                                             No specimen
                                                      250
                                                                                                    250   B               25


                                                            0                                         0                    0
                                                           C C




                                                                                                          C C




                                                                                                                                C C
                                                                                                               ox




                                                                                                                                     ox
                                                           oi il




                                                                                                         oi il




                                                                                                                               oi il
                                                                   x




                                                                                                                 x




                                                                                                                                       x
                                                                ox
                                                          n no




                                                                                                        n no




                                                                                                                              n no
                                                                do




                                                                                                              do




                                                                                                                                    do
                                                        FO FO




                                                                                                            FO




                                                                                                                                  FO
                                                                                                            ,d




                                                                                                                                  ,d
                                                             ,d
                                                      C Cor




                                                                                                    C Cor




                                                                                                                          C Cor
                                                             l,




                                                                                                           l,




                                                                                                                                 l,
                                                                                                      FO




                                                                                                                            FO
                                                       or




                                                                                                     or




                                                                                                                           or
                                                        TUMOR                                             LIVER                 COLON
xidative Stress
ation, UV, Fe and other
s or chemotherapeutic drugs                      Vit E




                             ids e:
                 PA




                          Lip mag
             or E           Damage:
          DHA inhibits eicosanoid
          AA                Proteins


                           Da
                            DNA                                                                   Fish oil
          synthesis from AA
             ROS                     activate




                                                                                       EP
          (Rose and Connolly, 1999) PO4




                                                                                         A
                                                                                                       Corn oil




                                                                                    PL

                                                                                         or
                                             IB-P       I BNF B




                                                                                      A2

                                                                                            A
                                                                         EPA




                                                                                                  A
                                                                                              or
                                                                                                 PL
          EPA effectively out-                                                      AA




                                                                                                   C
UFA                                                                                                 Vit. E
 HETE                                                      NFB       COX2
14,649    competes AA for COX                                           or            NSAIDS
xibrate                                                                LOX
               PPAR                                                          if from TBX2 enhances platelet aggregation
SAIDS
HEAS
          activity  cis retinol receptor                                    AA        LTB4 proinflammatory
          (Needleman, P., 1979; Yang, P., et al.,                        if from
                                                                                       PGE2 proproliferative
                                                                         EPA           PGE3 antiinflammatory
          2002)                                                                        LTB5 antiproliferative
                                                                      IL-1             TBX3 retards platelet aggregation
           Peroxisome                 PPREs NFB - REs induce
                                      genes     genes                 IL-6
            -oxidation                                                           proliferation
          EPA is a better substrate
 lipid binding proteins
                                          Nucleus                     IL-12 inflammation
                                                                      MMIF
       P450 isozymes
               COX
          for AOEs 2 than AA.                                         TNF

          (Yang, P., et al., 2002)
 Residual cancer cells must multiply for the tumor
     to reoccur or for metastatic sites to grow

LA and AA activate PKC stimulating mitosis (Hannun et al.,
1986)

N-3 fatty acids decrease activity of ras (Collett et al, 2001) and
AP-1 (Liu, et al., 2001)

AA products of COX and LOX increase mitosis; EPA and
DHA decreased mitosis and inhibited growth of breast and
colon cancer cells (Rose & Connolly, 1990; Buckman, 1991; Abou-
El-Ela, 1989)
             Functional apoptotic pathways help
                     control cell growth

COX-2 expression downregulates apoptotic pathway (Tsujii &
DuBois, 1995, Connolly & Rose, 1998)
NFB activation blocks apoptosis (Schwartz, 1999), n-3 fatty
acids block NFB activation
DHA inactivated Bcl-2 family genes and increased transcription
of genes and transcription factors that induce apoptosis
(Narayanan, et al, 2001; Chiu, et al., 1999)
     Terminally differentiated cells don’t multiply

Omega -3 fatty acids induced differentiation of breast cancer
cells (Wang, 2000)
     Angiogenesis must occur for tumors to grow
                  and metastasize


n-6 products of COX-2 and 12-LOX stimulate angiogenesis,
n-3 products do not
(Form & Auerback, 1983; Connolly & Rose, 1998)
  Omega 3 fatty acids decrease estrogen metabolism


PGE2 activates P450 aromatase to increase estrogen
production (Noble, et al. 1997)


Shift in estrogen metabolism towards 16-hydroxylation
increases the formation of aberrant hyperproliferation in
breast. Omega-3 supplements decreased 16-hydroxylation
(Osborne, et al. 1988)
                         Summary:
N-3 fatty acids may be detrimental to growth of
metastatic or residual cancer cells by:

• Altering eicosanoid metabolism
• Slowing cancer cell mitosis
• Increasing cancer cell death
• Inducing differentiation
• Suppressing angiogenesis
• Altering estrogen metabolism
Clinical evidence of benefit
Maximum tolerated dose

Burns, et al. Phase I clinical study of fish oil fatty acid
capsules for patients with cancer cachexia: cancer and
leukemia group B study 9473. Clin Cancer Res. 5:3842,
1999

Univ. of Iowa Cancer Center

0.3 g/kg/day - 70 kg patient can consume up to 21 g/day
Dose limiting toxicity was gastrointestinal, mainly diarrhea
Effects on cachexia

Barber, Fearon, Tisdale (Dept of Surgery, Univ of Edinburgh)

Various papers on cachexia in pancreatic cancer patients

• EPA supplement improved life span in pancreatic cancer
patients even with no other treatment

• Patients consuming an n-3 containing supplement gained
weight and quality of life was improved

• Patients excreted less IL-6 and less proteolysis inducing
factor
Breast cancer

Bougnoux (Univ Tours) –localized breast carcinoma
patients with higher levels of DHA in breast adipose tissue
responded better to chemotherapy. Level of n-3 fatty acids
was higher in patients with complete or partial remission
than in patients with no response or tumor progression
(p < 0.004)

Bagga (UCLA School of Medicine) – consumption of an n-
3 supplement for 3 months significantly changed
composition of breast adipose tissue. Breast adipose
composition changed more rapidly than gluteal adipose
composition.
Epidemiology studies
Simonsen et al. Am J Epidemiology 147:342, 1998
       4 of 5 centers n3/n6 EURAMIC = breast cancer risk

Goodstein et al. J Nutr 133:1409, 2003
        Premenopausal n3/n6 = non significant breast cancer risk
        Postmenopausal n3/n6 = significant breast cancer risk

Maillard et al. Int J Cancer 98:78, 2002
         DHA = significant breast cancer risk
         long chain n3/n6 = significant breast cancer risk

Bagga et al. Nutr Cancer 42:180, 2002
        N6 fat significantly higher in breast cancer cases
        for a given level of n6, higher EPA or DHA were protective

Pala et al J Natl Cancer Inst 93:1088, 2001
          DHA = significant breast cancer risk
Summary

• Preclinical studies indicate that n-3 fatty acids should
be beneficial for cancer treatment

• Mechanistic studies indicate feasible mechanisms for
the influence of n-3 fatty acids on tumor growth,
survival and response to chemotherapy

• Limited clinical studies that are available indicate that
n-3 fatty acids have been beneficial during cancer
therapy or may reduce risk for breast cancer
Bulldoggin’ Cancer

								
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