Resistance to chemotherapeutic
agents is a major problem in oncology, which limits the effectiveness of
anticancer drugs. Although various mechanisms by which cancer cells become
resistant to anticancer drugs in the microenvironment such as host factors,
specific genetics or epigenetic alterations in the cancer cells have been
identified, how to avoid these processes is still to be discovered. Some of the
intelligent ways cancerous cells dodge these drugs are, drug inactivation by
e.g. modification, partial degradation or complexing to another molecule
(Zahreddine H), alteration of drug targets by mutations or modification of
expression levels,. (Stavrovskaya AA. ), enhanced drug efflux involving the
reduction of drug accumulation(.Chang G, ) DNA damage repair or DNA damage
response, (Bonanno L.) and many more. In this study we focus on the mechanism
by which cancer cells develop resistance via autophagy and inhibition of cell
death (Holohan C)
As a major stressor, chemotherapeutics stimulate
cancer cells to try and maintain or restore metabolic homeostasis through
catabolic lysis of unnecessary proteins as well as aged or injured organelles.
This housekeeping mechanism is what is causing the problematic increase in prevalence
multi-drug resistance today. (Housman).
A completed autophagy ends by the phagolysosomal death
in an acidic lysosomal pH. Chloroquine and its derivative is such a drug, which
increase the pH preventing the digestive enzymes in the lysosome from activation.
In combination with fluorouracil (a anti-neoplastic drug), chloroquine help
sensitize cancer cells to this drug, and treatment with this combination was
more effective than with fluorouracil alone. (Sasaki K)
As described earlier, Warburg
effect appears to play a major role in cancer establishement and resistance.
Among the many enzymes participating in the glycolysis, LDH-A, the isoform of
lactate dehydrogenase is without doubt an remarkable anti-cancer target with
great developmental portential.
(Hirschhaeuser F). It is the key enzyme in anaerobic
glycolysis, by catalysing the conversion of pyruvate to lactate. When LDHA is
inhibited, instead of converting pyruvate to lactate and exporting it, more
excess pyruvate will enter the TCA cycle which requires more oxygen. Because
cancer cells depend on aerobic glycolysis, generating ATP faster and yielding
more precursors for use in proliferation, the TCA cycle and following
mitochdonrial oxidative phosphorylation pathway are impaired and dysfunctional.
(Pelicano H.). It is believed that the reason behind mitochondrial dysfunction
in cancer cells provide them with increased levels of reactive oxygen species
(ROS), in which mitochondrial respiration is particularly generative pathway of
these chemicals. (Ristow M. ) ROS production increases when the electron
transport chain is compromised, leading to leakage of electrons, which react
with oxygen to form superoxide. The exact mechanisms involved in the
mitochondrial dysfunction and increased ROS production are not well understood.
(Nemoto S.). One may wonder why cancerous cells would want to expose themselves
with ROS, and the suggested theory is that this may affect certain
redox-sensitive molecules and further lead to consequences such as stimulation
of cellular proliferations, differentiation, promotion of mutations and genetic
instability, and alteration in sensitivity to anti-cancer drugs. (Pelicano H,)
(Klaunig JE.). This theory supports the original theory of Otto Warburg about
the origin of cancer.
Metabolic symbiosis in cancer
another topic which revisits Otto Warburg’s theories. It is being studied how
the excessive lactate produced via LDHA conversion of pyruvate, which is
shuttled across the cell membranes of hypoxic cancer cells, is used in other
parts of the tumor by the neighbouring which are provided with a blood supply
delivering oxygen. (Nakajima, E. C.)
This information lays the foundation for the potential
use of LDH inhibitors to cause cancer cells to starve from their fuel sources
and therefore reversing Warburg effect and achieving a regained sensitivity to
the traditional cancer treatments limiting their metastatic potential and
leading to their cellular death and eradication. (Yang, Yang et al..)
Additionally, this study explores the combinatorial
effect of ATG gene knockout with LDH inhibition on cancer cell death. If any,
the importance of the ATG5 and ATG7 in cytoprotective autophagy stimulation,
provides a new target for cancer treatmen, possibly via an oncolytic
virotherapy, targeting those genes.