Introduo:

Como se sabe a quimioterapia, no tratamento do cancro, tens efeitos

adversos nos tecidos normais do paciente. Por esse motivo, tenta-se
encontrar outras formas de combater a atividade proliferativa enorme que
as clulas tumorais tm.
A distino funcional da atividade metablica entre as clulas normais e
clulas cancergenas pode ter uma nova utilidade teraputica.
Otto Warburg, vencedor do prmio Nobel em 1956, notou que os tumores
precisam de uma grande quantidade de glucose, em hipoxia, convertem-na
em lactato. Ao contrrio das clulas normais que recebem o ATP da gliclise
anaerbica, para os esforos normais. () Warburg effect!!!
Warburg effect - In oncology, the Warburg effect is the observation that
most cancer cells predominantly produce energy by a high rate
of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a
comparatively low rate of glycolysis followed by oxidation
of pyruvate in mitochondria as in most normal cells.
Malignant, rapidly growing tumor cells typically have glycolytic rates up to 200
times higher than those of their normal tissues of origin; this occurs even if
oxygen is plentiful.
(High glucose levels have been shown to accelerate cancer cell proliferation in vitro, while glucose
deprivation has led to apoptosis. These findings have initiated further study of the effects of
carbohydrate restriction on tumor growth. Clinical evidence shows that lower blood glucose levels in latestage cancer patients have been correlated with better outcomes.)

For example, leukemic cells, although residing within the blood stream at
high oxygen tension, exhibit the Warburg effect
Esta dependncia por glucose a base para a imagem clnica de cancros
metsticos, atravs da aplicao da PET (FDH-PET).
Grande consumo de glucose est relacionado com a agressividade do tumor
e um mau prognstico.

Fator indutivo da expresso da hipoxia:

Devido elevada proliferao das clulas tumorais, as clulas do interior do

tumor tendem a ficar privadas de oxignio, glucose e nutrientes
provenientes do sangue levando ao desenvolvimento da hipoxia.
A estabilizao de fatores indutivos de hipoxia (HIFs) HIF-1 e HIF-2, que
consistem em duas subunidades (alfa) e (Beta). HIF1(alfa) e HIF2(alfa)
ambos dimerizados com o HIF1(Beta) que se ligam aos genes dos elementos
promotores de hipoxia, iniciando o programa transcipcional para ultrapassar
o stress hipxico.
Devido ao efeito dos HIFs, o tumor produz fatores angiognicos como VEGF,
com o objetivo de aumentar a vascularidade dentro do stroma. Carcinoma
in situ impedido de promover angiognicos devido presena de uma
membrana basal.

Angiogenesis is the physiological process through which new blood vessels form from
pre-existing vessels.

Apenas quando isso breached, o tumor promove o crescimento de vasos

no interior do estroma e torna-se vascularizado e exposto a um ambiente
normoxico. Portanto nos primeiros estgios do cancro, a angiognese
falha no combate hipoxia.
H uma simbiose entre a zona exterior do tumor (bem oxigenada)
fosforilao oxidativa e a zona interna (esta zona produz o lactato) do
tumor que mantm a produo de lactato.
O lactato levado do interior do tumor para a zona exterior atravs de um
transportador de carboxilato 1 (MCT1), libertando as clulas da dependncia
de glucose, permitindo uma maior disponibilidade de glucose nas clulas em
estado de hipoxia.
Estes mecanismos tambm explicam a troca do efeito de warburg para a
fosforilao oxidativa sob condies limitantes de glucose nas clulas do
glioma.
Estes mecanismos tambm ainda no esto bem entendidos.
Warburg explicou que as mudanas no metabolismo celular do tumor era
devido a defeitos mitocondriais mas esta explicao no foi aceite.
Diversos estudos reportaram que ativao oncognica e supresso de
mutaes de tumores podem dar um aumento ao efeito de Warburg direta
ou indiretamente, atravs da ativao do HIF-1 independentemente da
hipoxia. (ativadores: ras, myc, Akt e p53)
Ativadores:
Ras promove a glicose
myc regula a expresso de vrios genes metablicos e interage
diretamente com a hexocinase 2.
Akt tem um papel na receo de glucose e a sua utilizao em cancros
mostram que apenas a ativao do Akt suficiente para levar a uma
receo de glucose elevada e o efeito de Warburg
p53 inibe a gliclise anaerbica e estimula a fosforilao oxidativa atravs
da ativao transcipcional do TIGAR (protena inibidora da gliclise); Perda
da p53 est relacionada com o aumento da atividade glicoltica.
Ativao do mTOR pode levar expresso no-hipoxica dos HIFs

HIF-1 regula a expresso de mais de 80 genes que so crticos no

metabolismo da glicose, sobrevivncia celular, angiognese tumoral,
invaso e metstase.
Praticamente todos os genes glicolticos so alvos transcipcionais do HIF.
A expresso da subunidade HIF-1(alfa) est sobre o controlo do mecanismo
de sinalizao do fator do crescimento envolvendo PI3K/Akt/mTOR e
Raf/MAPK.

HIF-1 is usually degraded under normoxic conditions but stabilized in tumors

even under non-hypoxic conditions as a consequence of oncogenic
activation of PI3K/Akt, src and ras or inactivation of tumor suppressor VHL
leading to the Warburg effect . Reduction of HIF-1 could be a promising
anticancer strategy.

Upregulation of glycolysis in cancer

Certainly the extrusion of accumulated lactate through multiple families of

H+ transporters to prevent acidosis induced apoptosis, creates an acidic
microenvironment harmless to themselves, yet fatal to competing
populations of normal cells which undergo apoptosis through p53- and
caspase-3-dependent mechanisms.
Simultaneously this may enhance the invasiveness and metastasis of tumor
cells which, as they occlude the intravascular space, probably experience
hypoxic episodes which will therefore favor cells that are glycolytic and
resistant to hypoxia- or acid-induced apoptosis.
Another requirement of cancer cells beyond ATP, is metabolite diversion
from the TCA cycle (Krebs cycle) for synthesis of macromolecular precursors
needed for cell division.
Tumors typically exhibit increased lipid, nucleotide and protein synthesis
capacity. Glycolytic intermediates including glucose-6-phosphate and
glyceraldehyde-3-phosphate can also be shunted into the pentose
phosphate pathway (PPP) for synthesis of ribose-5-phosphate (R-5-P) for
nucleotides and NADPH for fatty acid synthesis and prevention of oxidative
stress, as well as synthesis of pyruvate for amino acid metabolism
Interestingly tumors have a high requirement for amino acids which can
lead to depletion of glutamine in plasma - it has been suggested that
elevated glutaminase in tumor cells could provide glutamate for conversion
into (alfa)-ketoglutarate to compensate for the reduced flux of pyruvate into
the TCA cycle as well as citrate for lipid synthesis. Indeed, glutamine may be
a dominant energy source for tumors.
The high tumor glycolytic flux is facilitated by increased uptake of glucose
through HIF-1 induced over-expression of facilitative glucose transporters
such as GLUT1.

Controlo da
gliclise:

Hexocinase Piruvato cinaseFosfofructocinase

(PFK)
(HK)
(PK)

(1.)
Glucose is phosphorylated by HK which has four isoenzymes; at
least one of which (type II) is over-expressed in cancers.
Therapeutically, HK has been targeted with the non-metabolised glucose
analog, 2-deoxyglucose (2-DG), which entered clinical trials for treatment
of advanced lung, breast, prostate and gastric cancers and others such
as 5-thioglucose and mannoheptulose. Another drug that was thought to
block HK but may actually target glyceraldehyde-3-phosphate
dehydrogenase is 3-bromopyruvate, which causes severe depletion of
cellular ATP with significant anti-cancer effect in vivo.
Lonidamine, a derivative of indazole-3-carboxylic acid inhibits both
oxidative phosphorylation and the Warburg effect through interaction
with a mitochondrial bound HK - FDA approval is currently withdrawn due
to occurrence of liver problems.
(2.)
PFK is the second important rate limiting enzyme in glycolysis
and could potentially be a very effective target