Enhancement of cisplatin and etoposide cytotoxicity after all‐trans retinoic‐acid‐induced cellular differentiation of a murine embryonal carcinoma cell line

Abstract

The potential of a combination of differentiation induction and chemotherapy was analyzed. Treatment of the murine embryonal carcinoma (EC) cell line PCC4 in vitro with all-transretinoic acid (RA) was followed by exposure to cisplatin (CDDP) or etoposide (VP-16). The expression of EC-cell-specific markers decreased upon 96 hr exposure to 10(-9), 10(-8), 10(-7) and 10(-6) M RA, indicating a loss of embryonal phenotype of the cells, whereas expression of markers specific for cytokeratins and neurofilaments was increased after this treatment. These data suggest early somatic differentiation of PCC4 cells upon treatment with RA. Cellular growth rate of PCC4 cells was not affected by preincubation with RA at 10(-9) M for 96 hr, but was reduced at 10(-8) and 10(-7) M RA and inhibited at 10(-6) M RA. Culture of PCC4 cells in the presence of 10(-7) M RA for 96 hr led to accumulation in G1 of the cell cycle, whereas at 10(-8) M RA cell-cycle distribution was not affected. RA-treated and -untreated PCC4 cells were compared for CDDP and VP-16 sensitivity. Pre-treatment with 10(-9), 10(-8) and 10(-7) M RA increased CDDP sensitivity, resulting in a 1.9-, 2.7- and 2.6-fold decrease in the concentrations inhibiting survival by 50% (IC50s) respectively. Pre-treatment with 10(-8) and 10(-7) M RA increased VP-16 sensitivity 2.5- and 3.0-fold, respectively. Enhanced CDDP sensitivity at RA concentrations not affecting cell-cycle distribution was not attributable to changes in cellular platinum (Pt) accumulation, or to changes of Pt-DNA binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Multifactorial mechanism for the potentiation of cisplatin (CDDP) cytotoxicity by all-trans retinoic acid (ATRA) in human ovarian carcinoma cell lines

“…This effect on ovarian carcinoma cell proliferation was only observed when ATRA was added before CDDP and for a duration corresponding to the doubling time of the different ovarian adenocarcinoma cells. For NIHOVCAR3 cells, the optimal effect was observed at 48 h. These results are in line with those previously reported for small-cell lung cancer (Doyle et al, 1989), for an ovarian teratocarcinoma (Le Ruppert et al, 1992), for a murine embryonal carcinoma cell line (Guchelaar et al, 1993) and for epidermoid carcinoma (Sacks et al, 1995). Taken together, these observations suggest that ATRA induces a cascade of events facilitating CDDP cytotoxicity.…”

“…In this present work, we found that ATRA does not modify the platinum accumulation regardless of the sensitivity of the cells to this agent. Similarly, ATRA was not found to alter platinum accumulation in a murine embryonal carcinoma cell line (Guchelaar et al, 1993).…”

“…ATRA has been shown to increase the sensitivity of a murine embryonal carcinoma cell line to CDDP (Guchelaar et al, 1993) and to potentiate the cytotoxicity of CDDP, etoposide and bleomycin in a human ovarian teratocarcinoma (Le Ruppert et al, 1992). Furthermore, the combination of ATRA and CDDP has been reported to be beneficial in the treatment of head and neck tumours (Sacks et al, 1995).…”

Morphological and molecular evidence of differentiation during etoposide-induced apoptosis in human lymphoblastoid cells

“…44,45 There is also evidence that in non-haematopoietic cells, the association between differentiation and apoptosis results in enhancement of drug-induced cytotoxicity. 46,47 The observations reported here encourage further studies directed toward increasing the efficacy of chemotherapy for leukaemia which is otherwise restricted by the toxicity of agents which are primarily calculated to induce apoptosis in malignant cells.…”

Retinoids: present role and future potential

“…Indeed, in a variant cell line resistant to cisplatin but sensitive to ATRA, the IC 50 for cisplatin was reduced with combination therapy in the clonogenic assay. ATRA can also increase the sensitivity of a murine embryonal carcinoma cell line to cisplatin (Guchelaar et al, 1993), can potentiate the cytotoxicity of cisplatin, etoposide and bleomycin in a human ovarian teratocarcinoma (Le Ruppert et al, 1992) and is synergistic with cisplatin and 5-fluorouracil in squamous cell carcinoma cells (Sacks et al, 1995). Furthermore, enhanced antitumour efficacy of cisplatin is observed in combination with 9-cis retinoic acid in human oral squamous cell carcinoma xenografts in nude mice, with no change in systemic toxicity or dose tolerance of the individual agents (Shalinsky et al, 1996).…”