Antiproliferative effects of the arotinoid Ro 40-8757 in human gastrointestinal and pancreatic cancer cell lines: combinations with 5-fluorouracil and interferon-α

Abstract

Summary The arotinoid Ro 40-8757 was previously shown to inhibit the growth of a variety of human cancer cell lines derived from breast, lung and uterus. In view of the high incidence of human digestive cancers, and the slow progress in the development of new therapy, we examined in this paper several combinations between the new arotinoid Ro 40-8757, 5-fluorouracil (5FU) and interferon a-2a on the growth of nine human cancer cell lines derived from the gastrointestinal and pancreatic system. Half-maximal inhibition of cell proliferation by Ro 40-8757 was observed at concentrations ranging between 0.18 and 0.57 um, and increased up to 4.7 gM in retinoid-resistant CAPAN 620 pancreatic cells. All-trans-retinoic acid was 70 times less potent. The sensitivity of HT29-5FU-resistant colonic cells was similar to that observed in the parental cells, suggesting an action independent of pyrimidine metabolism. Ro 40-8757 did not induce any differentiation on HT29 cells, as suggested by ultrastructural analysis. The arotinoid did not interact with receptor signal transduction pathways under the control of serum components, such as growth factors as half-maximal inhibition of growth was similar in HT29-S-B6 cells cultured in the absence or presence of serum. Cell cycle analysis showed that Ro 40-8757 was not acting at a phase-specific transition in HT29 cells and, accordingly, did not induce overexpression of the protein kinase C (PKC)a isoform, or conversion of hyperphosphorylated p105 Rb into hypophosphorylated forms. However, the arotinoid induced significant accumulation of the dephosphorylated, active form of the tumour-suppressor protein. Combinations of Ro 40-8757 with 5FU and interferon a2a resulted in an additive but not synergistic antiproliferative action in HT29 cells. Our data support the interest in Ro 40-8757 as a potent anti-cancer drug, especially in combination therapy with 5FU and interferon, in gastrointestinal and pancreatic cancers, where new active therapeutic modalities are urgently needed.

Inhibition of oxidative phosphorylation underlies the antiproliferative and proapoptotic effects of mofarotene (Ro 40-8757) in Burkitt's lymphoma cells

“…This compound exhibited a significant degree of activity also at relatively low concentrations and against a wide panel of BL cell lines, regardless of the geographic origin of primary lymphoma and the type of c-myc-activating translocation. These findings are in keeping with previous observations demonstrating that Ro 40-8757 was one of the most active retinoids in inhibiting the growth of a variety of cell lines derived from carcinomas of different origin Uchida et al, 1994;Louvet et al, 1996). Moreover, consistent with what observed in other cellular systems, the drug did not induce any cell cycle phase-specific accumulation of BL cells Uchida et al, 1994;Louvet et al, 1996).…”

Retinoids cause apoptosis in pancreatic cancer cells via activation of RAR-γ and altered expression of Bcl-2/Bax

“…ATRA and 9cRA have previously been reported to have anti-proliferative effects and to modulate differentiation in pancreatic cancer cells (Rosewicz et al, 1995;Bold et al, 1996;Louvet et al, 1996). We have shown that they can also act as potent apoptosis-inducers (Pettersson et al, 2000), and in this study we have further elucidated the mechanisms behind this finding.…”

“…Responsiveness to retinoids in pancreatic cancer cells has previously been reported by different groups (Rosewicz et al, 1995;Bold et al, 1996;Louvet et al, 1996). A phase II trial of 13-cis retinoic acid and interferon-a in patients with advanced pancreatic carcinoma has also been completed and promising results with one partial remission and 14 out of 22 patients with stable disease for a median duration of 5 months were reported (Brembeck et al, 1998).…”

Differential and antagonistic effects of 9-cis-retinoic acid and vitamin D analogues on pancreatic cancer cells in vitro

“…Differential effects have also been shown in melanoma and colon cancer cells (Kane et al, 1996;Danielsson et al, 1999). In pancreatic cancer cells, responsiveness to both retinoids and vitamin D analogues have been reported previously (Rosewicz et al, 1995;Bold et al, 1996;Kawa et al, 1996;Louvet et al, 1996;Zugmaier et al, 1996;Colston et al, 1997). However, those studies have mainly assessed inhibition of cell growth and apoptosis has not been examined.…”