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Lung cancer is a leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the most prevalent lung cancer subtype. Ciclopirox olamine (CPX), an off-patent fungicide, has been identified as a new anticancer agent. Prexasertib (PRE), a Chk1 inhibitor, is in phase 1/2 clinical trials in various tumors. The anticancer effect of the combination of CPX with PRE on NSCLC cells is unknown. Here, we show that CPX is synergistic with PRE in inhibiting cell proliferation and inducing apoptosis of NSCLC (A549 and A427) cells. Combined treatment with CPX and PRE significantly increased the cell population in the G1/G0 and sub-G1 phases, compared to the single treatment with CPX or PRE. Concurrently, the combined treatment downregulated the protein levels of cyclins (A, B1), cyclin-dependent kinases 4, 6, 2 (CDK4, CDK6, CDK2), cell division cycle 25 B, C (Cdc25B, Cdc25C), and upregulated the protein levels of the CDK inhibitors p21 and p27, leading to decreased phosphorylation of Rb. In addition, the combined treatment increased DNA damage, evidenced by increased expression of γH2AX. In line with this, the combined treatment induced more apoptosis than either single treatment. This was associated with increased expression of DR4, DR5, Fas, and FADD and decreased expression of survivin, resulting in activation of caspase 8 and caspase 3 as well as cleavage of poly (ADP ribose) polymerase (PARP). Taken together, the results suggest that inhibition of Chk1 with PRE can enhance the anticancer activity of CPX at least partly by decreasing cell proliferation and increasing apoptosis in NSCLC cells. [ABSTRACT FROM AUTHOR]

The coexistence of numerous Mississippi-Valley-type (MVT) Zn–Pb deposits and (paleo) oil/gas reservoirs in the world suggests a close genetic relationship between mineralization and hydrocarbon accumulation. Xuequ–Shandouya middle MVT Zn–Pb deposits are mainly hosted in the Lower Cambrian Maidiping Member siliceous dolostone on the southwestern margin of the Yangtze Block, accompanied by large amount of bitumen in the orebodies. Therefore, this type of Zn–Pb deposit is a natural laboratory for studying the relationship between the mineralization and the accumulation of paleo-oil/gas reservoirs. The deposit is characterized by spheroidal and concentric banded sphalerite. In situ sulfur isotope studies are carried out to determine the sulfur sources, sulfate reduction mechanisms, and role of hydrocarbons in the zinc–lead mineralization process. According to the mineral paragenesis and relative temporal relationship, two mineralization stages (1 and 2) are identified. An in situ sulfur isotope analysis of spheroidal and concentric banded sphalerite particles from Stage 2 shows that there are the two following types of sulfur isotopes in the sphalerite: one with relatively invariable δ34S values in the core (+8.31 to +9.30‰), and the other with a gradual increase from the core margin (core) to the rim (+0.39 to +16.18‰). These two types reflect that they may have formed in different times, with first type forming in the early period of Stage 2, while the second type was formed in the late period of Stage 2. The sulfur isotopic data suggest the sulfur source of evaporated sulfate minerals and multiple formation mechanisms for reduced sulfur (H2S). In the early period of Stage 2 mineralization, the sulfate reduction mechanism is mainly a mixture of bacterial sulfate reduction (BSR) and/or thermochemical sulfate reduction (TSR), while a very small amount may come from the thermal decomposition of organic compounds (DOCs). In the late period of Stage 2, TSR is dominant, and the gradual increase in the δ34S value may be related to Rayleigh fractionation. The oil/gasreservoir not only acts as a reducing agent to provide the required hydrogen sulfide for zinc–lead mineralization through TSR or BSR, but also provides reduced sulfur for mineralization through the thermal decomposition of organic compounds directly. [ABSTRACT FROM AUTHOR]