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Retinoid-mediated inhibition of cell growth with stimulation of apoptosis in aggressive B-cell lymphomas
A Sundaresan1, K Claypool, K Mehta
1Department of Molecular Pathology, University of Texas M. D. Anderson Cancer Center, Houston 77030, USA.
Abstract:
Retinoids have been shown to modulate cell growth and differentiation in a variety of human tumor cell types, but their effects on B-cell non-Hodgkin's lymphomas (NHL-B) have not been explored. In this study, all-trans retinoic acid (ATRA) in the free form and liposome-encapsulated form (L-ATRA) were used to determine effects on fresh NHL-B patient cells as well as cell lines recently established from both HIV-negative and -positive NHL-B patient biopsies. Both ATRA and L-ATRA were found to inhibit cell proliferation in NHL-B cells. However, L-ATRA was found to be superior to free ATRA in inhibiting cell proliferation of NHL-B cells and resulted in greater than 90% cell growth inhibition in a dose-dependent manner. In addition, L-ATRA also induced high levels of apoptosis in NHL-B cells in vitro. To delineate the apoptotic pathways involved, the expression of the apoptosis suppressor oncogene bcl-2 was evaluated in different NHL-B cells with and without the t(14;18) chromosomal translocation. After L-ATRA exposure, more than a 50% reduction in the expression of bcl-2 protein was observed. bcl-2 message levels were also down-regulated in the L-ATRA-sensitive NHL-B cells. Bax protein levels were analyzed and found to be up-regulated in L-ATRA-sensitive NHL-B cells. Similar results were observed in sensitive AIDS/lymphoma cell lines. Experiments using an RAR-alpha antagonist (RO 41-5253) showed that both the proliferation inhibition and apoptosis induced by L-ATRA could be blocked in NHL-B cells. The findings of the present study indicate that L-ATRA may possess therapeutic potential in blocking cell proliferation, inducing apoptosis, and
Insights
Liposome-encapsulated all-trans retinoic acid (L-ATRA) effectively inhibits B-cell non-Hodgkin
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Retinoids modulate cell growth and differentiation in various human tumors.
- Effects of retinoids on B-cell non-Hodgkin's lymphomas (NHL-B) were previously unexplored.
- Liposomal encapsulation may enhance retinoid delivery and efficacy.
Purpose of the Study:
- To investigate the effects of all-trans retinoic acid (ATRA) and liposome-encapsulated ATRA (L-ATRA) on NHL-B cells.
- To determine the therapeutic potential of L-ATRA in NHL-B treatment.
- To elucidate the molecular mechanisms underlying L-ATRA's effects on NHL-B cells.
Main Methods:
- Treatment of fresh NHL-B patient cells and established cell lines with ATRA and L-ATRA.
- Assessment of cell proliferation inhibition and apoptosis induction.
- Evaluation of apoptosis-related gene and protein expression (bcl-2, Bax) and blockade with RAR-alpha antagonist.
Main Results:
- Both ATRA and L-ATRA inhibited NHL-B cell proliferation.
- L-ATRA demonstrated superior efficacy, achieving >90% growth inhibition dose-dependently and inducing significant apoptosis.
- L-ATRA downregulated bcl-2 expression and upregulated Bax expression, with effects blocked by an RAR-alpha antagonist.
Conclusions:
- Liposome-encapsulated all-trans retinoic acid (L-ATRA) shows significant therapeutic potential against B-cell non-Hodgkin's lymphomas.
- L-ATRA effectively inhibits NHL-B cell proliferation and induces apoptosis through modulation of bcl-2 and Bax.
- The findings support L-ATRA as a promising agent for NHL-B treatment, warranting further clinical investigation.