Uremic serum residue decreases SN-38 sensitivity through suppression of organic anion transporter polypeptide 2B1 in LS-180 colon cancer cells.

Pharmacokinetics of SN-38 in patients with end-stage kidney disease (ESKD) is partially varied because of fluctuations in transporters expression and/or function by high protein bound-uremic toxins concentration. The fluctuations may induce variations in anticancer drugs sensitivity to cancer cells. We aimed to clarify the variations in sensitivity of SN-38 to cancer patients with ESKD and investigate this mechanism, by human colon cancer cells exposed to uremic serum residue. LS180 cells were exposed to normal or uremic serum residue (LS/NSR or LS/USR cells) for a month. IC50 values of SN-38 in LS/NSR or LS/USR cells were calculated from viability of each cells treated SN-38. mRNA expression and intracellular SN-38 accumulation was evaluated by RT-PCR and HPLC-fluorescence methods, respectively. The IC50 value in LS/USR cells was higher than that in LS/NSR cells. Organic anion transporter polypeptide (OATP) 2B1 mRNA expression was lower in LS/USR cells than in LS/NSR cells, and SN-38 accumulation in LS/USR cells was lower than that in LS/NSR cells. Only co-treatment baicalin, which is OATP2B1 inhibitor, almost negated the difference in SN-38 accumulation between LS/NSR and LS/USR. Anticancer effects of substrates of OATP2B1, such as SN-38, were reduced in ESKD patients at the same plasma substrate concentration.

Light- and circadian-controlled genes respond to a broad light spectrum in Puffer Fish-derived Fugu eye cells.

Some cell lines retain intrinsic phototransduction pathways to control the expression of light-regulated genes such as the circadian clock gene. Here we investigated the photosensitivity of a Fugu eye, a cell line established from the eye of Takifugu rubripes, to examine whether such a photosensitive nature is present. Microarray analysis identified 15 genes that showed blue light-dependent change at the transcript level. We investigated temporal profiles of the light-induced genes, as well as Cry and Per, under light-dark, constant light (LL), and constant dark (DD) conditions by quantitative RT-PCR. Transcript levels of Per1a and Per3 genes showed circadian rhythmic changes under both LL and DD conditions, while those of Cry genes were controlled by light. All genes examined, including DNA-damage response genes and photolyase genes, were upregulated not only by blue light but also green and red light, implying the contribution of multiple photopigments. The present study is the first to identify a photosensitive clock cell line originating from a marine fish. These findings may help to characterize the molecular mechanisms underlying photic synchronization of the physiological states of fishes to not only daily light-dark cycles but also to various marine environmental cycles such as the lunar or semi-lunar cycle.