Topical Sunitinib ointment alleviates Psoriasis-like inflammation by inhibiting the proliferation and apoptosis of keratinocytes.

Psoriasis is a chronic auto-immune inflammation disease with skin lesions and abnormal keratinocyte proliferation. Sunitinib, a multi-targeted tyrosine kinase inhibitor, is known to selectively inhibit several growth factor receptors, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor and stem cell factor. It was reported that a patient with renal cell carcinoma (RCC) whose psoriatic lesion was resolved dramatically during treatment with Sunitinib, however, the mechanism is still unclear. We applied Sunitinib ointment to treat imiquimod-induced mouse model of psoriasis and found that Sunitinib ointment could alleviate imiquimod-induced psoriasis-like inflammation and reduce the Ki67 expression, while Sunitinib ointment couldn't reduce imiquimod-induced splenomegaly of the mouse model, then we concentrated on studying the effect of Sunitinib on the proliferation and apoptosis of keratinocytes, we cultivated HaCaT cells with epidermal growth factor (HaCaT/E cells) to represent as a state of highly proliferative psoriatic keratinocytes. We found that Sunitinib could inhibit the proliferation of Hacat/E cell in a time and concentration dependent manner by influencing the expression level of cell cycle protein D1, cycle protein E1, in addition, Sunitinib could induce the apoptosis of Hacat/E cell and up-regulate the expression of poly ADP-ribose polymerase (PARP). Sunitinib down-regulated the expression of phosphorylated signal transduction and activator of transcription 3 (p-Stat3) of Hacat/E cells significantly. We conclude that Sunitinib alleviates imiquimod-induced psoriasis-like inflammation by regulating the proliferation and apoptosis of HaCaT cells through inhibiting the expression of p-Stat3.

Relative dose intensity and therapy efficacy in different breast cancer molecular subtypes: a retrospective study of early stage breast cancer patients treated with neoadjuvant chemotherapy.

To investigate the relationship between chemotherapy dose intensity and therapy efficacy of different molecular subtypes. Clinical and pathological features of the patients with breast cancer were retreived from the hospital records. 315 patients were analyzed (251 showed clinical response, 38 acquired pCR). Patients with positive ER status, negative PR status, higher Ki67 level and higher RTDI had better therapy response. 13.5 and 84.5 % were identified the benchmark of Ki67 and RTDI, respectively. As the result of interior-subgroup comparison, luminal subgroups acquired better response rate when RTDI ≥ 84.5 %. In patients of luminal breast cancer, tumor size change arose from increasing of dose intensity and finally showed reached a plateau after RTDI ≥ 95 % (r (2) = 0.303, p < 0.001). As the result of intersubgroup comparison, TNBC patients were more likely to acquired better clinical and pathology response when RDTI < 84.5 %. Ki67 change arose sharply from increasing of dose intensity when RDTI < 84.5 % (r (2) = 0.656, p < 0.001), whereas the regression curve showed a terminal plateau in patients of RDTI ≥ 84.5 % (r (2) = 0.427, p < 0.001). Given lower RTDI, luminal patients are less likely to achieve response, and TNBC patients are associated with higher response rate. Dissimilar of therapy efficacy between luminal subtype and TNBC becomes inconspicuous as RTDI rises. Chemosensitivity may associate with dose intensity, especially in luminal subtypes, and tailored therapeutic strategies should be considered.

OSI-930 analogues as novel reversal agents for ABCG2-mediated multidrug resistance.

OSI-930, a dual c-Kit and KDR tyrosine kinase inhibitor, is reported to have undergone a Phase I dose escalation study in patients with advanced solid tumors. A series of fifteen pyridyl and phenyl analogues of OSI-930 were designed and synthesized. Extensive screening of these compounds led to the discovery that nitropyridyl and ortho-nitrophenyl analogues, VKJP1 and VKJP3, were effective in reversing ABC subfamily G member 2 (ABCG2) transporter-mediated multidrug resistance (MDR). VKJP1 and VKJP3 significantly sensitized ABCG2-expressing cells to established substrates of ABCG2 including mitoxantrone, SN-38, and doxorubicin in a concentration-dependent manner, but not to the non-ABCG2 substrate cisplatin. However, they were unable to reverse ABCB1- or ABCC1-mediated MDR indicating their selectivity for ABCG2. Western blotting analysis was performed to evaluate ABCG2 expression and it was found that neither VKJP1 nor VKJP3 significantly altered ABCG2 protein expression for up to 72 h. [(3)H]-mitoxantrone accumulation study demonstrated that VKJP1 and VKJP3 increased the intracellular accumulation of [(3)H]-mitoxantrone, a substrate of ABCG2. VKJP1 and VKJP3 also remarkably inhibited the transport of [(3)H]-methotrexate by ABCG2 membrane vesicles. Importantly, both VKJP1 and VKJP3 were efficacious in stimulating the activity of ATPase of ABCG2 and inhibited the photoaffinity labeling of this transporter by its substrate [(125)I]-iodoarylazidoprazosin. The results suggested that VKJP1 and VKJP3, specifically inhibit the function of ABCG2 through direct interaction with its substrate binding site(s). Thus VKJP1 and VKJP3 represent a new class of drugs for reducing MDR in ABCG2 over-expressing tumors.

RNA interference targeting the CD147 induces apoptosis of multi-drug resistant cancer cells related to XIAP depletion.

CD147 (basigin, EMMPRIN) is a widely distributed cell surface glycoprotein that belongs to the Ig superfamily. It is highly expressed on the surface of malignant tumor cells to promote their invasiveness and chemo-resistance. The present study aimed to reveal the anti-apoptotic effect of CD147 on the multi-drug resistant (MDR) phenotype of human oral squamous carcinoma cells (SCC) and its possible pathways. Data presented herein showed that MDR derivative SCC KB/V cell line expressed significantly higher CD147 and X-linked inhibitor of apoptosis (XIAP) than its sensitive counterpart KB cells by RT-PCR and Western blot analysis. Down-regulation of CD147 by transfection with CD147 siRNA resulted in decreased XIAP expression. Flow cytometric analysis and electron microscopic observation revealed differential cell apoptotic status related to CD147 expression. Additionally, chemo-sensitivity to 5-fluorouracil of KB/V was increased by CD147 silencing as measured by MTT colorimetric assay. These results suggest that inhibition of CD147 and subsequent XIAP depletion may have an anti-tumor effect through enhancing the susceptibility of cancer cells to apoptosis.