Title:Algerian Propolis Potentiates Doxorubicin Mediated Anticancer Effect Against Human Pancreatic PANC-1 Cancer Cell Line through Cell Cycle Arrest, Apoptosis Induction and P-Glycoprotein Inhibition
Volume: 18
Issue: 3
Author(s): Hassiba Rouibah, Wided Kebsa, Mesbah Lahouel*, Malek Zihlif, Mamoun Ahram, Bachaer Aburmeleih, Ebtihal Mustafa and Hamzeh J. Al-Ameer
Affiliation:
- Laboratory of Molecular Toxicology, Faculty of Sciences, University of Jijel, Jijel,Algeria
Keywords:
Algerian propolis, doxorubicin, PANC-1, P-gp, apoptosis, cell cycle, anticancer, potentiates.
Abstract: Background: Pancreatic cancer is one of the most aggressive and lethal cancers, with poor prognosis
and high resistance to current chemotherapeutic agents. Therefore, new therapeutic strategies and targets are
underscored. Propolis has been reported to exhibit a broad spectrum of biological activities including anticancer
activity.
Objective: This study was carried out to assess the possible efficacy of Algerian propolis on the antitumor effect
of doxorubicin on human pancreatic cancer cell line (PANC-1).
Methods: Modifications in cell viability, apoptosis and cell cycle progression, Pgp activity and intracellular
accumulation of DOX were monitored to study the synergistic effect of Algerian propolis on the antitumor effects
of DOX in PANC-1 cell line.
Results: Both propolis and its combination with doxorubicin inhibited cell growth in a dose-dependent manner
by inducing cell cycle arrest and apoptosis. In the presence of 100 μg/ml of propolis, the IC50 of DOX against
PANC-1 cells decreased by 10.9-fold. Propolis combined with DOX increased after 48h, the number of cells in
the G0G1 phase with dramatical increase in sub-G1 phase to reach 47% of total cells, corresponding to an increase
of senescence or apoptotic state of the cells. Dead cell assay with annexinV/PI staining demonstrated that
propolis and propolis-DOX treatment resulted in a remarkable induction of apoptosis as detected by flow cytometry.
It was interesting to note that propolis at its 5IC50 was found as the most potent inducer of apoptosis.
Our finding revealed that induced apoptosis in our conditions was caspase-3 and caspase-9 dependent. Flow
cytometry showed that propolis increased the accumulation of doxorubicin within PANC-1 cells. Moreover,
fluorescent intensity detection revealed that propolis remarkably increased the retention of rhodamine-123, 7-
fold compared to 3-fold of verapamil, the most effective P-gp inhibitor.
Conclusion: In conclusion, propolis sensitize pancreatic cancer cells to DOX via enhancing the intracellular
retention of DOX due to blocking the efflux activity of P-gp pump, inducing cell cycle arrest and increasing
apoptosis, finding that improuve the synergism of antitumor effect of Algerian propolis and DOX in pancreatic
cancer cell line. Therefore, Algerian propolis may be an effective agent in a combined treatment with doxorubicin
for increased therapeutic efficacy against pancreatic cancer.
