|
8th
International Inter University Scientific Meeting
Academy of Studenica
NEW
TRENDS IN DIAGNOSTICS AND THERAPY OF MALIGNANT TUMORS
Organizer:
Institute of Oncology Sremska Kamenica, Yugoslavia
Co-organizers: Institute
for Oncology and Radiology, Belgrade, Yugoslavia;
"Aristotel School", Thessaloniki, Greece
President: Prof.Dr.
Vladimir Vit. Baltić
|
|
|
|
SULFINOSINE
- THE NEW POTENTIALS IN TREATMENT OF LUNG CANCER
M.
Pešić, J. Milošević, S. Kanazir, Lj. Medić-Mijačević, Lj. Rakić,
S. Ruždijić
Institute for Biological Research "Siniša
Stanković", Department of Neurobiology and Immunology, Laboratory
of Molecular Neurobiology, Beograd, Yugoslavia
|
|
|
ABSTRACT
The
search for successful anticancer agents has been ongoing for decades.
It is very difficult to obtain a particular agent with all desirable
properties that would characterize it as successful chemotherapeutics.
Hoping to obtain compound less toxic to host cells and more effective
for anticancer therapy, the chemists have synthesized sulfinosine
(2-amino-9-ß-D-ribofuranosylpurine-6-sulfinamide). There are evidences
that suggest specific mechanism of sulfinosine (SF) action. SF has
the ability for binding glutathione and decreasing its concentration
in target cells. Consequently the actions of glutathione-S-transferase
(GST) and glutathione-peroxidase (GPX) are inhibited. The ability
of cancer cells for cellular detoxification is diminished and they
become vulnerable for action of other cytotoxic drugs. In accordance
with its mechanism of action, SF could sensitize resistant cancer
cells to standard chemotherapeutics. We have studied the potential
effects of SF on cell growth and proliferation, as well as on cell
cycle and cell death in vitro. Human non-small cell lung carcinoma
cells (NSCLC) and small cell lung carcinoma cells (SCLC) were used
as biological models for SF action. SF has demonstrated a dose dependent
inhibition of NSCLC and SCLC cell growth and proliferation with
IC50 values between 3.6 and 6.3 µM. Also, SF has caused typical
DNA laddering, a hallmark for apoptosis. The formation of free nucleosomes,
as well as, enzymatic labeling of fragmented DNA has confirmed apoptosis
involvement in SF action. In addition, flow-cytometric analysis
has showed the arrest in cell cycle progression at the G2M phase
and induction of apoptosis in both cell lines treated with SF. In
order to study the SF potential in reverting resistant phenotype,
further investigations were focused on the induction of resistant
NSCLC subline by repeated treatment with doxorubicin (Dox). The
established Dox-resistant NSCLC cells have showed 5-fold increase
in IC50 value in comparison with parental cells. Also, the expression
of mdr1 (encoding P-glicoprotein) and lrp (encoding lung-resistance-associated
protein) genes was evident in Dox-resistant, but not in parental
cells. Considering the suggested mechanism of SF action, we expect
to sensitize Dox-resistant cells for Dox treatment with the administration
of low concentrations of SF that should not impact cell growth.
Obtained results have shown that the biological effects of SF may
be due to modulation of cell growth, cell death, and cell cycle.
Further, we have established a biological model suitable for revealing
the potential of SF in reverting resistant phenotype.
|
|
|
Keywords:
Sulfinosine: Lung cancer: Cell growth: Apoptosis: Cell cycle:
Drug resistance |
|
|