is a way that cells can survive low oxygen / nutrient conditions
and other kinds of stress. The autophagy pathway can be
activated also when tumor cells are stressed by chemotherapy or
Whether activation of autophagy
allows tumor cells to survive therapy or is a
desirable mechanism for
initiating a non-apoptotic form of programmed cell death remains
It may depend on the type of cancer or perhaps on the mutations
that are driving its malignant behavior.
definition): is a process of self-cannibalization.
Cells capture their own cytoplasm and organelles and consume
them in lysosomes. The resulting breakdown products are
inputs to cellular metabolism, through which they are used
to generate energy and to build new proteins and membranes.
Autophagy preserves the health of cells and tissues by
replacing outdated and damaged cellular components with
fresh ones. In starvation, it provides an internal source of
nutrients for energy generation and, thus, survival. A
powerful promoter of metabolic homeostasis at both the
cellular and whole-animal level, autophagy prevents
degenerative diseases. It does have a downside,
howeverócancer cells exploit it to survive in nutrient-poor
Based on recent findings it has
been hypothesized that agents
that block autophagy may sensitize cancer cells to regular
treatments. One such agent is chloroquine (a drug
used to treat malaria). The testing of the treatment-sensitizing
properties of chloroquine are being evaluated in humans cancers.
Here we ask if this approach is
promising also for the treatment of some types or variants of
lymphoma. What follows is background on the autophagy pathway
and the rationale for testing agents that prevent cell survival
by autophagy in combination with regular treatments.
enhances therapy-induced apoptosis in a Myc-induced model of
suggests that autophagy can also represent an adaptive
strategy by which cells clear damaged organelles and survive
bioenergetic stress. Autophagy, by targeting cytoplasmic
proteins and organelles for lysosomal degradation, plays a
role in recycling organelles and proteins that may be
damaged by increased reactive oxygen species generated by
the cellular stress associated with activated oncogenes and
cancer therapies (7, 8). Autophagy also promotes the
survival of cells resistant to apoptosis when they are
deprived of extracellular nutrients or growth factors.
Treatment of such cells dependent on autophagy for survival
with the drug chloroquine (CQ) results in brisk cell death
These studies provide evidence that autophagy serves as a
survival pathway in tumor cells treated with apoptosis
activators and a rationale for the use of autophagy
inhibitors such as chloroquine in combination with therapies
designed to induce apoptosis in human cancers."
Overexpression of LC3A
autophagy protein in lymphoma [Hematol Oncol Stem Cell Ther.
2013] - PubMed - NCBI
EJP, 2009: Chloroquine and
its analogs: a new promise o... [Eur J Pharmacol. 2009] -
PubMed - NCBI
Autophagy inhibition in
combination cancer treatment [Curr Opin Investig Drugs.
2009] - PubMed - NCBI
The effective elimination of
cancer cells is compromised by mechanisms of resistance.
Such mechanisms have been variably ascribed to drug export
transporters, more effective DNA repair mechanisms compared
with healthy cells, singularly resistant stem cells,
resistance to apoptosis, self-sufficiency for growth factor
signaling and an angiogenic switch, as well as immunological
pathways associated with T-regulatory cells, myeloid-derived
suppressor cells or plasmacytoid dendritic cells.
In this review, the critically important process of
autophagy, which is a mechanism of cell survival in the
presence of genomic injury, endoplasmic reticulum stress,
oxidant stress, nutrient insufficiency and viral/bacterial
infection, is explored in the setting of cancer treatment.
Autophagy has recently been demonstrated as important for
conferring resistance to chemotherapy, radiation therapy and
Compounds are now available that can reverse autophagy,
including the antimalarial compounds chloroquine and
hydroxychloroquine, as well as the antidepressant agent
clomipramine. Other strategies for the reversal of autophagy
are based on the recent observation that the cytosolic
location of the chromatin-binding protein HMGB1
(high-mobility group box-1) is associated with sustained
autophagy. Targeting HMGB1 using platinum-containing
compounds, ethyl pyruvate or glycyrrhizin has also been used
to limit autophagy. Screening for new agents is ongoing,
which, coupled with conventional chemotherapeutic compounds,
may usher in a new generation of autophagy-inhibiting
ScienceDirect: Growth Factor
Regulation of Autophagy and Cell Survival in the Absence of