Sulfinosine enhances doxorubicin efficacy through synergism and by reversing multidrug resistance in the human non-small cell lung carcinoma cell line (NCI-H460/R)

Abstract

A resistant non-small cell lung carcinoma cell line-NSCLC (NCI-H460/R) was established in order to investigate the potential of sulfinosine (SF) to overcome multidrug resistance (MDR). The cytotoxicity of doxorubicin (DOX) in NCI-H460/R cells was enhanced by interaction with SF. SF improved the sensitivity of resistant cells to DOX when NCI-H460/R cells were pretreated with SF. Synergism was accompanied by the accumulation of cells in S and G(2)/M phases. Pretreatment with SF was more potent in improving the sensitivity to DOX than verapamil (VER). The decrease of mdr1 and topo II alpha expression (assessed by RT-PCR), was consistent with the DOX accumulation assay and cell cycle analysis. Also, SF significantly decreased intracellular glutathione (GSH) concentration. These results point to SF as a potential agent of MDR reversal and a valuable drug for improving chemotherapy of NSCLC.

Oleanolic Acid Initiates Apoptosis in Non-Small Cell Lung Cancer Cell Lines and Reduces Metastasis of a B16F10 Melanoma Model In Vivo

“…In a previous study, we showed that OA is also effective against MDR erythroleukemic cells overexpressing P-gp and its sensitive counterpart [24]. The present study was performed to examine the cytotoxic effects of OA on NSCLC cells (A549 and H460) that expressed both MRP1 [25], [26] and anti-apoptotic factors [7], [8], and to investigate the effects of this triterpene on pathways involved in drug resistance and the development of metastasis.…”

Purine analogs sensitize the multidrug resistant cell line (NCI-H460/R) to doxorubicin and stimulate the cell growth inhibitory effect of verapamil

“…In the present study we examined the effects of combinations of DOX and two purine analogs, SF and 8-Cl-cAMP on human sensitive (NCI-H460) and MDR resistant (NCI-H460/R) LCNEC cell lines. SF promotes the reversion of DOX resistance in NCI-H460/R both alone [8] and in combination with curcumin [12]. Synergistically enhanced effects of SF and 8-Cl-cAMP were observed in the human neuroblastoma cell line [16].…”

“…The ready formation of adducts between SF and sulfhydryl compounds (glutathione and cysteine) is probably responsible for the observed lowering of glutathione levels by SF and subsequent induction of cell death. These findings have stimulated investigations of MDR reversal by SF in the LCNEC cell line [8,12].…”

“…The inhibition of transport proteins are prerequisites for the effective reversion of the MDR phenotype. The potential of synthetic compounds and compounds originating from plants for MDR reversion are under scrutiny [7][8][9][10].…”

“…SF reverses DOX resistance in NCI-H460/R cells when applied alone [8] and in combination with curcumin [12]. 8-Cl-cAMP was shown to synergistically increase the growth-inhibitory effects of paclitaxel or cisplatin in a number of cell lines derived from human breast, lung, ovarian, colon, head carcinoma and melanoma [13,14].…”