- Cancer is characterized by
abnormal cell growth where both cell division and apoptosis (programmed
cell death) are impaired partly because of the impairment of the signaling
pathway of tumor suppressor agents, such as pRB.
- Cisplatin and 5-FU are
conventional drugs that act by inducing DNA damage or preventing DNA
production, leading to a reduction of cancer cells.
- Blocking CDKs (a family of
proteins responsible for pRB inactivation) activity is the mechanism of
action of new anti-cancer drugs when used with conventional drugs in
proteins that inactivate the tumor suppressor protein pRB, when used along with
the conventional anti-cancer drug cisplatin could increase tumor cell death,
but have an opposite disastrous effect when used along with 5-FU.
In a recent
study published in the scientific journal Translational Oncology
researchers from the Federal University of Rio de Janeiro (UFRJ), State
University of West Zone, (UEZO) and D'Or Institute for Research and Education
(IDOR) tested the therapeutic effect of a combination of conventional - common
anti-cancer agents - and new drugs - under clinical trials. "The results
were very exciting because the successful outcome depended on the chemotherapy
regimens. On the other hand, "wrong" combination of drugs could
elicit harmful effects," states Helena Borges, professor at Institute of
Biomedical Sciences of UFRJ, and study leader.
‘Using drugs that reverse the inactivation of tumor suppressor protein pRB, along with conventional drug cisplatin could kill cancer cells but have an opposite effect with 5-FU.’
when cells in a particular part of the body start growing and multiplying
abnormally. The disease in a later stage can spread or metastasize to organs
and regions outside the origin.
Cancer is one of the leading causes
of morbidity and mortality worldwide -
- Cancer affects 8.2 million people
- The number of new cases in the US
alone will reach 1.6 million in 2017
- Worldwide, the number of new cases
is expected to rise by about 70% over the next 2 decades
impact of a trillion dollars makes it critical to develop new drugs and other
novel treatment methods.
Tumor Suppressor Proteins
suppressor protein acts by suppressing the regulation of the cell cycle or by
promoting apoptosis (programmed cell death) or both. This keeps the cells from
dividing too fast or in an uncontrolled way and protects them from one step on
the path to cancer.
PRB Protein Retinoblastoma
protein (pRb) was the first
tumor-suppressor protein discovered in human retinoblastoma. Cancer's abnormal
pattern of cell growth depends on several signaling mechanisms inside the cells
multiple roles and recently it has also been implicated as a tumor-survival
Functions of pRB
- Inhibition of cell cycle
progression until a cell is ready to divide
- Stops other proteins from
triggering DNA replication (process of DNA making its own copies) before
- Interaction with other proteins to
influence cell survival, apoptosis, and the process by which cells mature
to carry out special functions (differentiation).
control cell division and prevent abnormal growth.
In cancer cells,
both cell division and apoptosis do not happen in a timely and organized manner, and are thus impaired because pRB and other tumor suppressor agents are not
fully available. PRB protein is dysfunctional in several major cancers.
about the central role of pRB in cancer makes it a potential target for
treatments with fewer side effects. Some new drugs that act on the pRB pathway,
enhancing its functioning and controlling cell growth to the right amount are
under clinical trials and may become alternative anti-cancer treatment soon.
Anti-cancer or Chemotherapeutic Agents
Most of the
anti-cancer drugs used today were developed more than 50 years ago, when there
was poor knowledge of the cancer-related cellular mechanisms. Two of the
chemotherapeutic drugs, cisplatin and 5-FU act by inducing DNA damage or
prevent DNA production, thus causing a reduction in the number of cancer cells.
is a well-known chemotherapeutic drug
that was discovered in 1845 and licensed for medical use in 1978/1979. It is
effective against various types of cancers and has been used for the treatment
of numerous human cancers including bladder, head and neck, lung, ovarian, and testicular
. Its mode of action is by interfering with DNA repair
mechanisms, causing DNA damage, and subsequently inducing cell death in cancer
of drug resistance, toxicity and numerous undesirable side effects such as
severe kidney problems either other platinum-containing anti-cancer drugs have
been substituted for cisplatin or it is now used in combination therapies with
Fluorouracil or 5-FU Fluorouracil
is used to treat cancer; it was
patented in 1956 and came into medical use in 1962. Fluorouracil is given
systemically for breast, colorectal, oesophageal, stomach, pancreatic and skin
principally by inhibiting the action of thymidylate synthase (TS) that is
responsible for the synthesis of the pyrimidine thymidine, a nucleoside
required for DNA replication. This "thymineless death" causes rapidly dividing
cancerous cells to undergo cell death.
Rio de Janeiro studied whether cisplatin and 5-FU
- Would be able to interfere with
- Have an impact on tumor cell death
induction and on the standard treatment against cancer
is the sixth most common cause of
cancer-related death worldwide and pRB's key role in its signaling pathway is
was first assessed in human esophageal biopsies from non-tumoral tissue,
esophageal pre-cancer and advanced stages of disease. This helped in observing
a positive correlation between pRB expression and cancer progression; that is
,greater pRB inactivation was found when the esophageal tumor was in a more
result reinforces the notion that impaired pRB signaling contributes for the
esophageal cancer progression", points Prof. Borges.
The second part
of the study focused on a family of proteins called cytokine-dependent
kinases or CDKs
that are responsible for pRB inactivation. CDK acts by
phosphorylation of pRb, thus alleviating the inhibitory effect of pRB and
promoting cell cycle progression.
CDKs combined with conventional drugs, such as cisplatin and 5-FU, increase
cell death, and make the treatment more effective? This is what the researchers wanted to clarify.
Results of The Study
CDKs' activity was the mechanism of action of new anti-cancer drugs under
clinical trials, the analyses revealed two different effects depending on the
chemotherapeutic drug they were paired with. If the cells were treated with
- Cisplatin, the mortality of tumor
- 5-FU, the resistance of esophageal
cancer cells increased, and thus, their death rates decreased
"The results bring attention to
studies that investigate the combination of CDKs' inhibitors and conventional
anti-cancer drugs. CDKs' inhibitors seem to enhance the treatment, but
depending on the situation, combining them with 5-FU can be disastrous"
says Prof. Borges.
highlights the importance of gathering knowledge of cell biology in order to
strategically identify and test anti-cancer drugs according to Stevens Rehen,
researcher from IDOR and professor at the Institute of Biomedical
Sciences/UFRJ, co-author of the study.
New studies have
been conducted to investigate the effects of specific CDKs' inhibitors on new
combinations of several types of cancer.
- 1. Rossana C. Soletti, Deborah Biasoli, Nathassya A.L.V. Rodrigues, João M.A. Delou, Renata Maciel, Vera L.A. Chagas, Rodrigo A.P. Martins, Stevens K. Rehen, Helena L. Borges. Inhibition of pRB Pathway Differentially Modulates Apoptosis in Esophageal Cancer Cells. Translational Oncology, 2017; 10 (5): 726 DOI: 10.1016/j.tranon.2017.06.008