Low doses of cisplatin or gemcitabine plus Photofrin/photodynamic therapy: Disjointed cell cycle phase-related activity accounts for synergistic outcome in metastatic non–small cell lung cancer cells (H1299)

Abstract

We compared the effects of monotherapy (photodynamic therapy or chemotherapy) versus combination therapy (photodynamic therapy plus a specific drug) on the nonsmall cell lung cancer cell line H1299. Our aim was to evaluate whether the additive/synergistic effects of combination treatment were such that the cytostatic dose could be reduced without affecting treatment efficacy. Photodynamic therapy was done by irradiating Photofrinpreloaded H1299 p53/p16-null cells with a halogen lamp equipped with a bandpass filter. The cytotoxic drugs used were cis-diammine-dichloroplatinum [II] (CDDP or cisplatin) and 2V,2V-difluoro-2V-deoxycytidine (gemcitabine). Various treatment combinations yielded therapeutic effects (trypan blue dye exclusion test) ranging from additive to clearly synergistic, the most effective being a combination of photodynamic therapy and CDDP. To gain insight into the cellular response mechanisms underlying favorable outcomes, we analyzed the H1299 cell cycle profiles and the expression patterns of several key proteins after monotherapy. In our conditions, we found that photodynamic therapy with Photofrin targeted G 0 -G 1 cells, thereby causing cells to accumulate in S phase. In contrast, lowdose CDDP killed cells in S phase, thereby causing an accumulation of G 0 -G 1 cells (and increased p21 expression). Like photodynamic therapy, low-dose gemcitabine targeted G 0 -G 1 cells, which caused a massive accumulation of cells in S phase (and increased cyclin A expression). Although we observed therapeutic reinforcement with both drugs and photodynamic therapy, reinforcement was more pronounced when the drug (CDDP) and photodynamic therapy exert disjointed phase-related cytotoxic activity. Thus, if photodynamic therapy is appropriately tuned, the dose of the cytostatic drug can be reduced without compromising the therapeutic response. [Mol Cancer Ther 2006;5(3):776 -85]

The effect of genistein for preventing granulose cell injury induced by cisplatin

“…Moreover, other study have shown that CDDP combined with DNA caused cell damage (Olas et al, 2006;Salsbury et al, 2006), which could cause apoptosis to some extent. Our study showed that high dose of CDDP caused apoptosis of granulosa cells of ovary at S phase, which was consistent with previous reports that chemotherapeutics have significant role in interfering with cell cycle (Horowitz et al, 2004;Crescenzi et al, 2006;Xu et al, 2007;Hara et al, 2006). Genistein has been shown to have many biological activities, such as anti-cancer, anti-oxidant, antiinflammatory actions and inhibition of tyrosine-specific protein kinases (Akiyama et al, 1987;Rusin et al, 2010;Park et al, 2010;Zhang et al, 2008).…”

Synergistic Anticancer Activity of 5-Aminolevulinic Acid Photodynamic Therapy in Combination with Low-dose Cisplatin on Hela Cells

“…Combination treatment showed dramatically increased cytotoxicity on Hela cells compared with PDT and cisplatin alone (P<0.05) (Figure 3). This is in agreement with other experiments, in which cytotoxic drug such as cisplatin, gemcitabine were found to act synergistically with PDT in vitro (Crescenzi et al, 2004;Crescenzi et al, 2006). In Hela cells, cell viability induced by PDT + 5 mg/L cisplatin was only 6.607±2.656% and which was significantly lower than combination treatment with 0.1, 1.0, 2.5 mg/L cisplatin.…”

“…A few preclinical studies have been performed to establish potential advantages produced through combination of cisplatin with PDT (Crescenzi et al, 2004;Crescenzi et al, 2006;Uehara et al, 2006;Compagnin et al, 2010;Ge et al, 2011;Kim et al, 2012). He et al (2008) have explored the effects of 5-Aminolevulinic acid photodynamic therapy (5-ALA/PDT) and possible mechanisms involved in the treatment of cervical cancer in vivo an vitro .…”

In vitroexpansion of human breast cancer epithelial and mesenchymal stromal cells: optimization of a coculture model for personalized therapy approaches

“…For growth experiments with drugs, FBS was substituted with DCC-FBS supplemented with testosterone at 10 À7 mol/L as a substrate for aromatase. To experimentally ascertain the dose of drugs required to attain a submaximal effect, dose-response curves were constructed according to a ''fixed dose method'', as previously described (21,22). The growth curve responses of the control cell lines and of cocultured cells were evaluated after treatment with different concentrations of formestane or herceptin alone.…”