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Briz et al. Liver cancer chemoresistance

or stimulation of alternative routes (MOC-3); ability by anti-apoptotic target genes of HIF-1, which include
[7]
of tumor cells to repair drug-induced modifications Bcl-xL, Bcl-2, Mcl-1, NF-kB and BIRC5; (4) HIF-1-
in the target molecule, usually DNA (MOC-4); and dependent decrease of the DNA-damage response-
the activation or inhibition of intracellular signaling activated senescence, which is partly accountable
pathways that lead to a change in the balance for the anti-tumor effect of different chemotherapeutic
[7]
between pro- and anti-apoptotic factors favoring tumor agents; (5) HIF-1-dependent induction of autophagy
cell survival (MOC-5). Nevertheless, novel information which confers a survival advantage to tumor cells
on the role of several adaptive mechanisms involved and protects them from drug-induced death signals.
[7]
in liver cancer chemoresistance has emerged in the HIF-1 target genes such as BNIP3 (Bcl-2/adenovirus
last few years. These regard the existence of cancer E1B 19-kDa interacting protein 3) and BNIP3L (Bcl-
stem cells with particularly poor sensitivity to anticancer 2/adenovirus E1B 19-kDa interacting protein 3 like),
drugs, the interference with the inflammatory processes members of the so-called BH3-only subfamily of Bcl-2
and cytokine expression, cellular autophagy status, family proteins that antagonize the activity of the pro-
changes in tumor microenvironment and phenotipic survival proteins Bcl-2 and Bcl-xL, have suggested
transition of cancer. This situation recommends to be involved in the hypoxia-induced autophagy. A
[8]
considering at least two additional MOC that we role of HIF-1 independent mechanisms in hypoxia-
propose to be classified into MOC-6 and MOC7. induced drug resistance in cancer cells has also
been reported. These mechanisms are still poorly
CHEMORESISTANCE DUE TO CHANGES understood, but pathways involving phosphoinositol-
IN TUMOR MICROENVIRONMENT (MOC-6) 3-kinase (PI3K), nuclear factor kappa-B (NF-kB),
cycloxygenase-2 (COX-2), activator protein-1 (AP-1),
Two peculiar features characterizing tumor c-Jun, Pim-1, and STAT-3 have been reviewed and
microenvironment, i.e. hypoxia and acidity, play an have been suggested to participate in MOC-6. [2]
important role in tumor progression, metastasis and
response to chemotherapy. Several in vitro studies Regarding the role of acidic environment in MOC-6,
have demonstrated that hypoxia induces enhanced it should be taken into account that, as a result of
resistance to antitumor drugs, such as cisplatin, the active acid production through glycolysis, which
doxorubicin, etoposide, melphalan, 5-fluorouracil, occurs in tumor cells even in the presence of oxygen,
[2]
+
gemcitabine, and docetaxel. The family of hypoxia- there is the need of extruding a large amount of H to
inducible transcription factors (HIFs) represents the survive. The mechanisms activated in tumor cells to
main mediator of the hypoxic response and is widely efficiently eliminate protons include up-regulation of
upregulated in human cancers. HIF-1 and to a lesser ion pumps, such as vacuolar H -ATPase (V-ATPase),
+
+
extent HIF-2, the oxygen-regulated HIF isoforms, have and transporters, such as Na /H exchanger (NHE),
+
been associated with chemotherapy failure. Thus, together with an increased turnover of acidic vesicles.
HIF-1 inhibition reverses multidrug resistance in colon The low extracellular pH (pHo) may severely affect
[3]
cancer cells. Moreover, silencing HIF-1 in tumor drug uptake. For instance, acidic pHo reduces the
cells results in increased sensitivity to anticancer uptake of chemotherapeutic drugs that behave as
[4]
drugs. Several mechanisms and pathways that may weak bases, such as anthracyclines and Vinca
underlay HIF-1-mediated chemotherapy resistance alkaloids, and, hence, reduces their cytotoxicity by
in tumor cells under hypoxia have been described. preventing these compounds from reaching their
[9]
These include: (1) HIF-1-mediated regulation of drug intracellular targets. Thus, the possibility that basic
efflux through the activation of transport proteins drugs could be protonated and neutralized in a higher
such as the multidrug resistance 1 (MDR1) gene proportion by the acidic pHo of tumor environment
(ABCB1), the multidrug-resistance-associated has to be considered. [10] It has been demonstrated
protein 1 (MRP1, gene symbol ABCC1) and the that compounds able to disrupt tumor pH homeostasis
lung resistance protein (LRP) or major vault protein may reverse multidrug resistance phenotype
(MVP, gene symbol MVP); (2) HIF-1-mediated and indirectly inhibit the growth of the tumors.
[5]
[6]
inhibition of drug-induced DNA damage. This effect Thus, treatment with sodium bicarbonate induced
is partially mediated via transcriptional down-regulation alkalinization of pHo and tumor growth inhibition in
[9]
[6]
of topoisomerase II in human tumor cells; (3) HIF-1 animal models. Moreover, lysosomotropic agents
functions as a robust suppressor of apoptosis and that induce modification of the pHo vs. intracellular pH
functional interference with HIF-1 results in enhanced (pHi) gradient and alkalinization of intracellular acidic
cell death upon treatment with chemotherapeutic vesicles may reverse anthracycline resistance in
+
agents in tumors of different origins. The molecular chemoresistant cells. [11] In addition, H -pump inhibitors
nature of this phenomenon was mostly accounted for induce drug-resistance reversion in chemoresistant
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