DTX-P7, a peptide-drug conjugate, is highly effective for non-small cell lung cancer.

Despite tremendous success of molecular targeted therapy together with immunotherapy, only a small subset of patients can benefit from them. Chemotherapy remains the mainstay treatment for most of tumors including non-small cell lung cancer (NSCLC); however, non-selective adverse effects on healthy tissues and secondary resistance are the main obstacles. Meanwhile, the quiescent or dormant cancer stem-like cells (CSLCs) are resistant to antimitotic chemoradiotherapy. Complete remission can only be realized when both proliferative cancer cells and quiescent cancer stem cells are targeted. In the present research, we constructed a cooperatively combating conjugate (DTX-P7) composed of docetaxel (DTX) and a heptapeptide (P7), which specifically binds to cell surface Hsp90, and assessed the anti-tumor effects of DTX-P7 on non-small cell lung cancer. DTX-P7 preferentially suppressed tumor growth compared with DTX in vivo with a favorable distribution to tumor tissues and long circulation half-life. Furthermore, we revealed a distinctive mechanism whereby DTX-P7 induced unfolded protein response and eventually promoted apoptosis. More importantly, we found that DTX-P7 promoted cell cycle reentry of slow-proliferating CSLCs and subsequently killed them, exhibiting a "proliferate to kill" pattern. Collecitvely, by force of active targeting delivery of DTX via membrane-bound Hsp90, DTX-P7 induces unfolded protein response and subsequent apoptosis by degrading Hsp90, meanwhile awakens and kills the dormant cancer stem cells. Thus, DTX-P7 deserves further development as a promising anticancer therapeutic for treatment of various membrane-harboring Hsp90 cancer types.

Proteasome Inhibitor YSY01A Abrogates Constitutive STAT3 Signaling via Down-regulation of Gp130 and JAK2 in Human A549 Lung Cancer Cells.

Proteasome inhibition interfering with many cell signaling pathways has been extensively explored as a therapeutic strategy for cancers. Proteasome inhibitor YSY01A is a novel agent that has shown remarkable anti-tumor effects; however, its mechanisms of action are not fully understood. Here we report that YSY01A is capable of suppressing cancer cell survival by induction of apoptosis. Paradoxically, we find that YSY01A abrogates constitutive activation of STAT3 via proteasome-independent degradation of gp130 and JAK2, but not transcriptional regulation, in human A549 non-small cell lung cancer cells. The reduction in gp130 and JAK2 can be restored by co-treatment with 3-methyladenine, an early-stage autophagy lysosome and type I/III PI3K inhibitor. YSY01A also effectively inhibits cancer cell migration and lung xenograft tumor growth with little adverse effect on animals. Thus, our findings suggest that YSY01A represents a promising candidate for further development of novel anticancer therapeutics targeting the proteasome.

Compound porcine cerebroside and ganglioside injection attenuates cerebral ischemia-reperfusion injury in rats by targeting multiple cellular processes.

BACKGROUND: Compound porcine cerebroside and ganglioside injection (CPCGI) is a neurotrophic drug used clinically to treat certain functional disorders of brain. Despite its extensive usage throughout China, the exact mechanistic targets of CPCGI are unknown. This study was carried out to investigate the protective effect of CPCGI against ischemic neuronal damage in rats with middle cerebral artery occlusion (MCAO) reperfusion injury and to investigate the neuroprotective mechanisms of CPCGI. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were subjected to MCAO surgery for 2 hours followed by reperfusion. The rats were administered CPCGI once a day for 14 days after reperfusion, and behavioral tests were performed 1, 3, 7, and 14 days post MCAO. Hematoxylin-eosin staining was used to measure infarct volume, and immunohistochemical analysis was performed to determine the number of NeuN-positive neurons in the ischemic cortex penumbra. Finally, the relative expression levels of proteins associated with apoptosis (Bcl-2, Bax, and GADD45α), synaptic function (Synaptophysin, SNAP25, Syntaxin, and Complexin-1/2), and mitochondrial function (KIFC2 and UCP3) were determined by Western blot. RESULTS: CPCGI treatment reduced infarct size, decreased neurological deficit scores, and accelerated the recovery of somatosensory function 14 days after MCAO. In addition, CPCGI reduced the loss of NeuN-positive cells in the ischemic cortex penumbra. In the ischemic cortex, CPCGI treatment decreased GADD45α expression, increased the Bcl-2/Bax ratio, augmented Synaptophysin, SNAP25, and Complexin-1/2 expression, and increased the expression of KIFC2 and UCP3 compared with sham rats 14 days after MCAO reperfusion injury. CONCLUSION: CPCGI displays neuroprotective properties in rats subjected to MCAO injury by inhibiting apoptosis and improving synaptic and mitochondrial function.