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Platinum-based chemotherapeutics are widely used for cancer treatment but are frequently limited because of dosage-dependent side effects and drug resistance. To attenuate these drawbacks, a series of novel platinum(IV) prodrugs (15a-18c) were synthesized and evaluated for anti-cancer activity. Among them, 17a demonstrated superior anti-proliferative activity compared with oxaliplatin (OXA) in the cisplatin-resistant lung cancer cell line A549/CDDP and OXA-resistant colon cancer cell line HCT-116/OXA but showed a lower cytotoxic effect toward human normal cell lines HUVEC and L02. Mechanistic investigations suggested that 17a efficiently enhanced intracellular platinum accumulation, induced DNA damage, disturbed the homeostasis of intracellular reactive oxygen molecules and mitochondrial membrane potential, and thereby activated the mitochondrion-dependent apoptosis pathway. Moreover, 17a significantly induced ferroptosis in HCT-116/OXA via triggering the accumulation of lipid peroxides, disrupting iron homeostasis, and inhibiting solute carrier family 7 member 11 and glutathione peroxidase 4 axial pathway transduction by inhibiting the expression of the phosphorylated signal transducer and activator of transcription 3 and nuclear factor erythroid 2-related factor 2. Moreover, 17a exerted remarkable in vivo antitumor efficacy in the HCT-116/OXA xenograft models but showed attenuated toxicity. These results indicated that these novel platinum(IV) complexes provided an alternative strategy to develop novel platinum-based antineoplastic agents for cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Masson SAS.)

We have reported a lentivector which could effectively induce HBV-specific cytotoxic T lymphocytes (CTLs). Avasimibe is an inhibitor of acetyl-CoA acetyltransferase-1 (ACAT1), and has been shown to enhance T lymphocyte cytotoxicity on tumor cells. However, the role of avasimibe in lentivector-induced HBV-specific T cytotoxic response remains unknown. Based on previous study, we constructed an integration-deficient lentivector LVDC-ID-HBV (harboring HBcAg expression), and the in vitro experiments showed that the combination of avasimibe exhibited better efficacy in inducing HBV-specific CTL responses including cell proliferation, production of cytokines, as well as CTL killing activities. Mechanism experiments showed that increasing cell membrane cholesterol levels by MβCD-coated cholesterol or ACAT1 inhibition efficiently promoted TCR clustering, signaling transduction and immunological synapse formation, thereby mediating augmented CTL responses. Nevertheless, the depletion of plasma membrane cholesterol with MβCD led to obviously decreased CTL responses. The avasimibe-mediated strengthened immune effects were also determined in animal experiments and the results were in agreement with those from the in vitro research. In particular, the in vivo CTL killing activities were identified by the CFSE or BV-labeled splenocyte lysis assay. Moreover, the experiments in HBV transgenic mice showed that the LVDC-ID-HBV plus avasimibe group demonstrated the lowest serum HBsAg and HBV DNA levels, as well as the lowest expression of HBsAg and HBcAg in liver tissues. We concluded that the HBV-specific CTL immune responses could be potentiated by avasimibe through regulating plasma membrane cholesterol levels. Avasimibe may be a potential adjuvant for lentivector vaccine against HBV infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Developing multifunctional platinum(IV) prodrugs via integrating bioactive pharmacophores into one entity is an attractive strategy to ameliorate the defects of platinum(II) drugs. Herein, a series of indole-chalcone derivative-ligated platinum(IV) complexes were synthesized and evaluated for their anticancer activities. Among them, optimal complex 17a exerted superior activity compared to that of cisplatin (CDDP) against the tested cells but showed lower cytotoxicity toward human normal lung cells. Detailed mechanisms demonstrated that 17a significantly enhanced intracellular accumulation, induced DNA damage, and inhibited migration in A549/CDDP cells. Furthermore, 17a efficiently disturbed the tubulin-microtubule system, initiated reactive oxygen species (ROS)-mediated endoplasmic reticulum stress, and activated a mitochondrion-dependent apoptosis signaling pathway. Besides, 17a was superior to free drugs or their combination in inhibiting cancer growth in A549/CDDP xenografts without inducing obvious side effects. The physical mixture of 16a and CDDP was almost identical to 17a but showed apparent systematic side effects. In summary, our studies may provide an efficient treatment regimen for CDDP resistance.

The cyclometalated iridium(III) compounds have been intensively studied for health-related applications due to their outstanding luminescent properties and multiple anticancer modes of action. Herein, two iridium(III) compounds Ir-1 and Ir-3 containing glutathione S-transferase inhibitor (GSTi) were developed and studied together with two unfunctionalized compounds Ir-2 and Ir-4 as a comparison. Biological study indicated that GSTi-bearing complexes Ir-1 and Ir-3 exert a synergistic effect on the inhibition of cancer cells. The photophysical properties of Ir-1 ∼ Ir-4 were investigated by UV/vis absorption and fluorescence spectroscopy and rationalized with TD-DFT calculations. As expected, GSTi-bearing complexes Ir-1 and Ir-3 exhibited considerable cytotoxicity against both A549 and cisplatin-resistant A549/cis cancer cells, much higher than the unfunctionalized iridium compounds Ir-2 and Ir-4. Further study indicated that Ir-1 and Ir-3 mainly localize in the mitochondria of tumor cells, and exert their cytotoxicity via generating ROS and inhibiting GST activity. The flow cytometry investigations demonstrated that Ir-1 and Ir-3 can arrest the cell cycle in S phase and induce the cell death through apoptosis process. Overall, the complexation of GST inhibitors with cyclometalated iridium(III) agents provides an effective way for potentiating the cytotoxicity of iridium(III) anticancer agents and resensitizing the efficacy against cisplatin resistant cancer cells., Competing Interests: Declaration of Competing Interest The authors declared that they have no conflicts of interest to this work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Operative treatment on oral cancer greatly damages the chewing and language function of the patient, we aim to find better solution with fewer side effects. The anti-tumor effects of Liquiritigenin (LQ) have been explored in kinds of cancers, but not in oral cancer. In this study, our purpose is to reveal the effects of LQ on oral cancer and the associated mechanism.Cell proliferation was examined through 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and 5-Ethynyl-2'- deoxyuridine (EDU) staining. Cell apoptosis in cells and tissues were assessed by flow cytometry and terminal dexynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, respectively. Expressions of AKT and light chain 3 (LC3) were detected through Immunofluorescence. In addition, xenograft model was established by injecting the CAL-27 cells (2 × 10 6 ) subcutaneously into the right flanks of mice. Expression of Ki67 and Beclin1 in tissues was valued by Immunohistochemistry (IHC).We found that cell viability of CAL-27 and SCC-9 was effectively inhibited by LQ. Besides, obvious cell apoptosis and cell autophagy were induced by LQ. In addition, PI3K/AKT/mTOR pathway was sharply inactivated by LQ in oral cancer cells. Corresponding in vivo experiments demonstrated that tumor growth was largely restricted, cell apoptosis was augmented and autophagy was enhanced by LQ. What is more, phosphorylation of AKT in tumor tissues could also be inhibited by LQ. LQ inhibited the progression of oral cancer through inducing autophagy-associated apoptosis via PI3K/AKT/mTOR pathway inhibition, revealing a new possible scheme for the treatment of oral cancer.

Erlotinib, an EGFR tyrosine kinase inhibitor has been introduced into cancer chemotherapy. However, the therapeutic effects of erlotinib in hepatocellular carcinoma (HCC) remain vaguely understood. Our previous study found that a hypoxia-mediated PLAGL2-EGFR-HIF-1/2α signaling loop in HCC decreased response to erlotinib. The current study has demonstrated that the combination of erlotinib and 2ME2 exerted synergistic antitumor effects against HCC. Further investigation showed that erlotinib increased the expression level of EGFR, HIF-2α, and PLAGL2, which contributes to the insensitivity of hypoxic HCC cells to erlotinib. The simultaneous exposure to 2ME2 effectively inhibited the expression level of EGFR, HIF-2α, and PLAGL2 that was induced by erlotinib. This contributes to the synergistic effect of the two therapeutic agents. Furthermore, the combination of erlotinib and 2ME2 induced apoptosis and inhibited the stemness of hypoxic HCC cells. Our findings potentially explain the mechanism of HCC insensitivity to erlotinib and provide a new strategy of combining EGFR and HIF1/2α inhibitors for HCC treatment., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A new series of millepachine derivative containing aminophosphonate ester moieties were designed and synthesized, and evaluated for their anticancer activities using MTT assay. Among all the compounds, compound 9m exhibited the most potent cytotoxic activity against all tested human cancer cell lines including multidrug resistant phenotype, which inhibited cancer cell growth with IC 50 values ranging from 0.85 to 3.09 μM, respectively. In addition, its low cytotoxicity toward human normal liver cells HL-7702 and sensitivity toward to doxorubicin or cisplatin-resistant cells indicated the possibility for cancer therapy. Furthermore, 9m significantly induced cell apoptosis and cell cycle arrest in G2/M phase and dramatically disrupted the microtubule organization. Moreover, a decrease in MMP, an increase in reactive oxygen species (ROS) generation and Bax/Bcl-2 ratio, accompanied by activated caspase-3 and -9, were observed in HepG-2 cells after incubation with 9m, indicating that the mitochondrial pathway was involved in the 9m-mediated apoptosis., (Copyright © 2019. Published by Elsevier Inc.)

Here we report that three platinum(IV) prodrugs containing a tubulin inhibitor CA-4, as dual-targeting platinum(IV) prodrug, were synthesized and evaluated for antitumor activity using MTT assay. Among them, complex 9 exhibited the most potent antitumor activity against the tested cancer lines including cisplatin resistance cancer cells, and simultaneously displayed lower toxicity compared to cisplatin, respectively. Moreover, complex 9, in which was conjugated to an inhibitor of tubulin at one axial position of platinum(IV) complex, could effectively enter the cancer cells, and significantly induce cell apoptosis and arrest the cell cycle in A549 cells at G2/M stage, and dramatically disrupt the microtubule organization. In addition, mechanism studies suggested that complex 9 significantly induced reactive oxygen species (ROS) generation and decreased mitochondrial trans-membrane potential (MMP) in A549 cells, and effectively induced activation of caspases triggering apoptotic signaling through mitochondrial dependent apoptosis pathways., (Copyright © 2019. Published by Elsevier Inc.)

A novel compound, Cou-platin, composed of 7-hydroxycoumarin and a platinum(IV) moiety derived from cisplatin was designed and synthesized. Significantly, Cou-platin exhibited more potent in vitro antitumor activity against all tested cancer cell lines than that of cisplatin, which was mainly attributed to the liberation of cisplatin and 7-hydroxycoumarin upon reduction with a biomolecular agent. Besides, cellular accumulation of Cou-platin was dramatically increased among several cancer cells in contrast to cisplatin. Flow cytometry study revealed that Cou-platin arrested cell cycle at G2 phase and induced cell apoptosis. Western blots results indicated that it not only activated cell apoptosis pathway, but also inhibited extracellular regulated protein kinases/mitogen-activated protein kinase pathway. In vivo tests showed that Cou-platin, at equimolar dose to cisplatin, could inhibit tumor growth in nude mouse HCT116 tumor xenograft models almost as cisplatin and oxaliplatin, but with less toxicity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Several Pt(IV) prodrugs containing SAA, a histone deacetylases inhibitor, were designed and prepared for multiply targeting genomic DNA, histone deacetylases and PARP-1. The resulting Pt(IV) prodrug had significantly strong antiproliferative activity against the tested cancer cell lines, especially SAA1, derived from the conjugation of cisplatin and SAA, had potent ability to overcome cisplatin resistance. Under the combined action of DNA platination and inhibition of HDACs and PARP-1 activity, the cytotoxic activity of SAA1 was 174-fold higher than cisplatin against cisplatin-resistant SGC7901/CDDP cancer cells. The mechanism of action of SAA1 was preliminarily investigated, in which cellular uptake, cell apoptosis and cell cycle arrest as well as western blot analysis were made by treating SAA1 with SGC7901/CDDP cells. Besides, HDACs inhibition activity and PARP-1 enzyme inhibition of SAA1 were also studied., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Platinum-based anticancer drugs are one of the most widely used anticancer chemotherapeutics in oncology. Lonidamine (LND) could increase the response of human tumor cells to platinum(II) drugs in preclinical studies by working on the mitochondria. Herein, five platinum(IV) prodrugs conjugated with their potentiator LND are prepared, and most of the target complexes achieve improved anticancer activities compared with their platinum(II) precursors. Notably, Pt(NH 3 ) 2 (LND)Cl 3 (complex 1 ) derived from cisplatin achieve significantly improved anticancer activities against LNCaP cells and could trigger cancer cell death via an apoptotic pathway and the cell cycle arrest mainly at S phases. And the induction of apoptosis by complex 1 in LNCaP cells is closely associated with mitochondrial function disruption and reactive oxygen species (ROS) accumulation. Moreover, it is possessed of the ability to overcome cisplatin-resistance. Further research revealed that complex 1 could be easily reduced to release its platinum(II) precursor and axial ligand by ascorbic acid. All the results provid evidence to support the design strategy of conjugating platinum complexes with its potentiator to improve their anticancer effect. [ABSTRACT FROM AUTHOR]

A Pt(IV) prodrug, Cx-platin, containing CX-4945 (a CK2 inhibitor) as an axial ligand was designed and prepared by targeting CK2 to disrupt DNA damage response. In vitro study indicated that Cx-platin had superior cytotoxicity to cisplatin against a number of cancer cell lines with distinct CK2-expressed levels, caused CK2-overexpressed cancer cells death via suppressing CK2-mediated DNA damage repair and reversed cisplatin resistance. Mechanistic investigation suggested that the potent antitumor activity of Cx-platin resulted from its major suppression of CK2-phosphorylated MDC1 to combine FHA domain of aprataxin to DNA double strand breaks (DSBs) caused by improved cellular uptakes of Pt and ATM deactivation. Further in vivo tests exhibited that Cx-platin displayed high tumor inhibition rates, increased weight gain, and hardly toxicity effects in contrast to cisplatin. [ABSTRACT FROM AUTHOR]