Dual inhibition of oxidative phosphorylation and glycolysis to enhance cancer therapy.

Dual suppression of oxidative phosphorylation (OXPHOS) and glycolysis can disrupt metabolic adaption of cancer cells, inhibiting energy supply and leading to successful cancer therapy. Herein, we have developed an α-tocopheryl succinate (α-TOS)-functionalized iridium(III) complex Ir2, a highly lipophilic mitochondria targeting anticancer molecule, could inhibit both oxidative phosphorylation (OXPHOS) and glycolysis, resulting in the energy blockage and cancer growth suppression. Mechanistic studies reveal that complex Ir2 induces reactive oxygen species (ROS) elevation and mitochondrial depolarization, and triggers DNA oxidative damage. These damages could evoke the cancer cell death with the mitochondrial-relevant apoptosis and autophagy. 3D tumor spheroids experiment demonstrates that Ir2 owned superior antiproliferation performance, as the potent anticancer agent in vivo. This study not only provided a new path for dual inhibition of both mitochondrial OXPHOS and glycolytic metabolisms with a novel α-TOS-functionalized metallodrug, but also further demonstrated that the mitochondrial-relevant therapy could be effective in enhancing the anticancer performance.

Consolidating Organometallic Complex Ir-CA Empowers Mitochondria-Directed Chemotherapy against Resistant Cancer via Stemness and Metastasis Inhibition.

Cancer treatment has faced severe obstacles due to the smart biological system of cancer cells. Herein, we report a three-in-one agent Ir-CA via attenuation of cancer cell stemness with the down-regulated biomarker CD133 expression from the mitochondria-directed chemotherapy. Over 80% of Ir-CA could accumulate in mitochondria, result in severe mitochondrial dysfunctions, and subsequently initiate mitophagy and cell cycle arrest to kill cisplatin-resistant A549R cells. In vitro and in vivo antimetastatic experiments demonstrated that Ir-CA can effectively inhibit metastasis with down-regulated MMP-2/MMP-9. RNA seq analysis and Western blotting indicated that Ir-CA also suppresses the GSTP1 expression to decrease the intracellular Pt-GS adducts, resulting in the detoxification and resensitization to cisplatin of A549R cells. In vivo evaluation indicated that Ir-CA restrains the tumor growth and has minimal side effects and superior biocompatibility. This work not only provides the first three-in-one agent to attenuate cancer cell stemness and simultaneously realize anticancer, antimetastasis, and conquer metallodrug resistance but also demonstrates the effectiveness of the mitochondria-directed strategy in cancer treatment.

Functional Upgrading of an Organo-Ir(III) Complex to an Organo-Ir(III) Prodrug as a DNA Damage-Responsive Autophagic Inducer for Hypoxic Lung Cancer Therapy.

The efficiency of nitrogen mustards (NMs), among the first chemotherapeutic agents against cancer, is limited by their monotonous mechanism of action (MoA). And tumor hypoxia is a significant obstacle in the attenuation of the chemotherapeutic efficacy. To repurpose the drug and combat hypoxia, herein, we constructed an organo-Ir(III) prodrug, IrCpNM, with the composition of a reactive oxygen species (ROS)-inducing moiety (Ir-arene fragment)-a hypoxic responsive moiety (azo linker)-a DNA-alkylating moiety (nitrogen mustard), and realized DNA damage response (DDR)-mediated autophagy for hypoxic lung cancer therapy for the first time. Prodrug IrCpNM could upregulate the level of catalase (CAT) to catalyze the decomposition of excessive H2O2 to O2 and downregulate the expression of the hypoxia-inducible factor (HIF-1α) to relieve hypoxia. Subsequently, IrCpNM initiates the quadruple synergetic actions under hypoxia, as simultaneous ROS promotion and glutathione (GSH) depletion to enhance the redox disbalance and severe oxidative and cross-linking DNA damages to trigger the occurrence of DDR-mediated autophagy via the ATM/Chk2 cascade and the PIK3CA/PI3K-AKT1-mTOR-RPS6KB1 signaling pathway. In vitro and in vivo experiments have confirmed the greatly antiproliferative capacity of IrCpNM against the hypoxic solid tumor. This work demonstrated the effectiveness of the DNA damage-responsive organometallic prodrug strategy with the microenvironment targeting system and the rebirth of traditional chemotherapeutic agents with a new anticancer mechanism.

Cyclometalated iridium(III) complexes as anti-breast cancer and anti-metastasis agents via STAT3 inhibition.

Breast cancer is the most commonly diagnosed cancer and second­leading cause of cancer deaths in women. Signal transducer and activator of transcription 3 (STAT3) plays a critical role in promoting breast cancer cell proliferation, invasion, angiogenesis, and metastasis, and the high expression of STAT3 is related to the occurrence and poor chemotherapy sensitivity of breast cancer. Iridium(III) complexes Ir-PTS-1- 4 containing a pterostilbene-derived ligand were synthesized to inhibit the STAT3 pathway in breast cancer. Ir-PTS-4 inhibited the proliferation of breast cancer cells by suppressing the expression of phosphorylated STAT3 and STAT3-related cyclin D1, arresting cell cycle in the S-phase, inducing DNA damage and reactive oxygen species (ROS) generation, eventually leading to autophagic cell death. The cell metastasis and invasion were also inhibited after Ir-PTS-4 treatment. Besides, Ir-PTS-4 exhibited excellent anti-proliferation activity in 3D multicellular tumor spheroids, showing potential for the treatment of solid tumors. This work presents the rational design of metal-based anticancer agents to block the STAT3 pathway for simultaneously inhibiting breast cancer proliferation and metastasis.

Self-Assembly Mitochondria-Targeting Donor-Acceptor Type Theranostic Nanosphere Activates ROS Storm for Multimodal Cancer Therapy.

The rational design of cancer theranostics with natural diagnostic information and therapeutic behavior has been considered to be a big challenge, since common theranostics from photothermal and photodynamic therapy need to be activated with external stimuli of photoirradiation to enable the chemotherapeutic effects. In this contribution, we have designed and synthesized a series of simple theranostic agents, TPA-N-n (n = 4, 8, 12), which could accumulate at the tumor site over 48 h and indicate superior antiproliferative performance in vivo. TPA-N-n was constructed with electron donor triphenylamine-acceptor benzothiadiazole-mitochondria-targeting moiety pyridinium. Complex TPA-N-8 indicated the best cytotoxicity to cancerous HeLa cells, with an IC50 value of 4.3 µM, and could self-assemble to a nanosphere with a size of 161.2 nm in the DMSO/PBS solution. It is worth noting that TPA-N-8 could accumulate in the mitochondria and produce major ROS species O2•- and OH• as well as small amounts of 1O2 without photoirradiation. Oxidative DNA damage is initiated due to the imbalance of intracellular redox homeostasis from the significant ROS storm. Multimodal synergistic therapy for HeLa cells was activated, as the PINK1-mediated mitophagy from the damaged mitochondria and DNA damage responsive (DDR) induced necroptosis and autophagy. This work not only provided a successful D-A type theranostic agent with superior anticancer performance from multimodal synergistic therapy but also further demonstrated the high efficacy of a mitochondria-targeting strategy for cancer treatment.

Switching the Mode of Cell Death between Apoptosis and Autophagy by Histone Deacetylase 6 Inhibition Levels.

Inhibition of histone deacetylase (HDAC) has been demonstrated to be an effective strategy for cancer treatment. In this work, we have developed a new agent Ir-VPA, which exhibits the cell death mode switching between apoptosis and autophagy due to the distinct level of HDAC6 inhibition. Ir-VPA indicates the best anticancer activity to HeLa cells, and could be hydrolyzed due to the high expression of the esterase in HeLa cells. Ir-VPA could accumulate in nuclei, induce severe DNA damages and cell cycle arrest at G2/M phase. The anticancer mechanism of Ir-VPA to HeLa cells was dependent on the HDAC6 inhibitory performance, as the caspase dependent apoptosis at low concentration (IC50 ) and autophagy with the autophagy flux blockage at high concentration (2×IC50 ). This is resulted from the distinct inhibitory levels of HDAC6, as moderate/complete inhibition at the concentration of IC50 /2×IC50 .In the presence of autophagic inhibitor chloroquine, the apoptotic population elevated from 32.7 % to 61.7 %, indicating that Ir-VPA could activate apoptotic process through the autophagolysosome fusion inhibition. Ir-VPA also exhibits excellent antiproliferative behavior to 3D HeLa multicellular tumor spheroids (MCTSs). This work not only provided a new HDAC6 inhibitor and novel anticancer mechanism for the effective treatment of cervical cancer, but also demonstrated the strategy to conjugate the metal fragment with active organic drug to enhance the anticancer performance.

C-reactive protein as a non-linear predictor of prolonged length of intensive care unit stay after gastrointestinal cancer surgery.

BACKGROUND: The relationship between C-reactive protein (CRP) levels and prolonged intensive care unit (ICU) length of stay (LoS) has not been well defined. AIM: To explore the association between CRP levels at ICU admission and prolonged ICU LoS in gastrointestinal cancer (GC) patients after major surgery. METHODS: A retrospective study was performed to quantify serum CRP levels and to establish their association with prolonged ICU LoS (≥ 72 h) in GC patients admitted to the ICU. Univariate and multivariate regression analyses were conducted, and restricted cubic spline curves with four knots (5%, 35%, 65%, 95%) were used to explore non-linearity assumptions. RESULTS: A total of 408 patients were enrolled. Among them, 83 (20.3%) patients had an ICU LoS longer than 72 h. CRP levels were independently associated with the risk of prolonged ICU LoS [odds ratio (OR) 1.47, 95% confidence interval (CI) 1.00-2.17]. Restricted cubic spline analysis revealed a non-linear relationship between CRP levels and OR for the prolonged ICU LoS (P = 0.035 for non-linearity). After the cut-off of 2.6 (log transformed mg/L), the OR for prolonged ICU LoS significantly increased with CRP levels. The adjusted regression coefficient was 0.70 (95%CI 0.31-1.57, P = 0.384) for CRP levels less than 2.6, whereas it was 2.43 (95%CI 1.39-4.24, P = 0.002) for CRP levels higher than 2.6. CONCLUSION: Among the GC patients, CRP levels at ICU admission were non-linearly associated with prolonged ICU LoS in survivors. An admission CRP level > 2.6 (log transformed mg/L) was associated with increased risk of prolonged ICU LoS.

A New Strategy to Fight Metallodrug Resistance: Mitochondria-Relevant Treatment through Mitophagy to Inhibit Metabolic Adaptations of Cancer Cells.

Metabolic adaptations can help cancer cells to escape from chemotherapeutics, mainly involving autophagy and ATP production. Herein, we report a new rhein-based cyclometalated IrIII complex, Ir-Rhein, that can accurately target mitochondria and effectively inhibit metabolic adaptations. The complex Ir-Rhein induces severe mitochondrial damage and initiates mitophagy to reduce the number of mitochondria and subsequently inhibit both mitochondrial and glycolytic bioenergetics, which eventually leads to ATP starvation death. Moreover, Ir-Rhein can overcome cisplatin resistance. Co-incubation experiment, 3D tumor spheroids experiment and transcriptome analysis reveal that Ir-Rhein shows promising antiproliferation performance for cisplatin-resistant cancer cells with the regulation of platinum resistance-related transporters. To our knowledge, this is a new strategy to overcome metallodrug resistance with a mitochondria-relevant treatment.

Ankylosing Spondylitis Complicated with Atlantoaxial Dislocation and Destruction of the Dens and Lateral Atlantoaxial Joint: A Case Report.

CASE: Non-neoplastic bone destruction, known as Andersson lesion, is not rare in ankylosing spondylitis (AS) and always appeared as bone destruction and sclerosis in the vertebral body-intervertebral disc region. The Andersson lesion has been reported mostly in the thoracic and lumbar spine and rarely in the lower cervical spine. We surgically treated a patient with AS complicated with atlantoaxial dislocation and destruction of dens and lateral atlantoaxial joint, which was similar to the Andersson lesion. CONCLUSIONS: AS can cause destructive lesion in the upper cervical spine. Posterior reduction, removal of the lesion, and fusion were possible approaches for the treatment of this destructive lesion.

Posterior Screw-Rod Fixation and Selective Axial Loosening for the Treatment of Atlantoaxial Instability or Dislocation Caused by Os Odontoideum: A Case Series for a Single Posterior Approach.

OBJECTIVE: To evaluate the effect of screw-rod fixation and selective axial loosening in the treatment of atlantoaxial instability or dislocation (including reducible and irreducible) caused by os odontoideum (OO) via a single posterior approach. METHODS: A consecutive series of patients with OO surgically treated in our hospital were retrospectively analyzed. For atlantoaxial instability and reducible atlantoaxial dislocation, C1-C2 screw-rod fixation and fusion were performed. OO combined with irreducible atlantoaxial dislocation was reduced after posterior axial loosening, followed by screw-rod fixation and fusion. The general information, clinical data, and radiographic data were compared between the 2 different procedures. RESULTS: There were 41 patients with an average age of 40.6 ± 21.7 years. All the patients underwent posterior reduction and C1-2 screw rod fixation, 6 with axial loosening and 35 without axial loosening. The clinical manifestations and radiographic data significantly improved after the operation with a low rate of complications. Except for clivus-canal angle and visual analogue score of cervical pain, there were no differences in clinical and radiographic data between the 2 procedures. CONCLUSIONS: Posterior screws-rod fixation and selective axial loosening is appropriate for treating OO complicated with atlantoaxial instability or dislocation (including reducible and irreducible) without the need for anterior decompression.

Antiangiogenic effect of crocin on breast cancer cell MDA-MB-231.

BACKGROUND: Crocin is the major chemical constituent of the Chinese herb saffron. A number of studies have indicated that crocin induces an antitumor effect by inhibiting proliferation and inducing the apoptosis of tumor cells. However, the effect of crocin on tumor angiogenesis remains unknown. METHODS: The effects of prolonged crocin exposure on breast cancer cell MDA-MB-231, human umbilical vein endothelial cells (HUVECs) and mice were examined. RESULTS: Crocin had a profound effect on the morphology and proliferation rate of MDA-MB-231 and HUVECs. Furthermore, crocin induced apoptosis and cell cycle arrest at the G2/M phase in MDA-MB-231 cells in a dose-dependent manner. This confirms that crocin induces the inhibition of HUVECs. Furthermore, the expression of CD34 in tumor tissues decreased after crocin treatment. CONCLUSIONS: Crocin has an anti-angiogenesis effect that may be correlated to the decreased expression of CD34. Crocin is likely to be involved in the regulation of molecules in the angiogenesis pathway.

[Experimentation of the relationship between medial or lateral patellar stabilizer and patellofemoral stabilization].

OBJECTIVE: To study the contribution of medial or lateral stabilizer to the stability of the patella, to explore the function and effect of releasing the LPR clinically and to provide a biomechanical basis for the clinical treatment of patellar instability(PI). METHODS: The quadriceps femoris of 6 fresh human cadaver knees were loaded to simulate a normal condition of muscle strength. First the loading force was measured and recorded, which subluxated the patella with the different degrees of knee flexion. Intervention 1:released the medial patellar retinaculum(MPR) to simulate pathologic conditions, then repeated the above manipulates and recorded the loading force. Intervention 2:released the LPR furthermore to simulate clinical surgical treatment, then repeated the above manipulates and recorded the loading force. RESULTS: After releasing the MPR, the loading force which subluxated the patella were decreased obviously, and there were significant differences between the two groups(P<0.05). The above loading force was further decreased after the further release of LPR, but the difference was not significant(P>0.05). CONCLUSIONS: MPR plays an important role in maintaining the stability of the patella and in the normal trajectory of the patellofemoral joint. The attention should be paid to the repair or reconstruction of the MPR in the treatment for patella recurrent lateral dislocation subluxation. Releasing the LPR is not a best choice.

Expression and Clinical Significance of Sushi Domain- Containing Protein 3 (SUSD3) and Insulin-like Growth Factor-I Receptor (IGF-IR) in Breast Cancer.

BACKGROUND: To investigate the expression of insulin-like growth factor-I receptor (IGF-IR) and sushi domaincontaining protein 3 (SUSD3) in breast cancer tissue, and analyze their relationship with clinical parameters and the correlation betweenthe two proteins. MATERIALS AND METHODS: The expression of IGF-IR and SUSD3 in 100 cases of breast cancer tissues and adjacent normal breast tissues after surgery was detected by immunohistochemical technique MaxVisionTM, and the relationship with clinical pathological features was further analyzed. RESULTS: The positive rate of IGF-IR protein was 86.0% in breast cancer, higher than 3.0% in adjacent normalbreast tissue (P<0.05) .The positive expression rate of SUSD3 protein was 78.0% in breast cancer, higher than 2.0% in adjacent normal breast tissue (P<0.05). The expression of IGF-IR and SUSD3 was related to estrogen receptor and pathological types (P<0.05),but not with age, stage, the expression of HER-2 and Ki-67 (P>0. 05). The expression of IGF-IR and SUSD3 in breast cancer tissue was positively related (r= 0.553, P<0.01). CONCLUSIONS: The expression of IGF-IR and SUSD3 may be correlated to the occurrence and development of breast cancer. The combined detection of IGF-IR, SUSD3 and ER may play an important role in judging prognosis and guiding adjuvant therapy after surgery of breast cancer.

[Analysis of RASSF1A promoter hypermethylation in serum DNA of non-small cell lung cancer].

OBJECTIVE: To detect the hypermethylation status of RASSF1A promoter in serum DNA of non-small cell lung cancer (NSCLC) patient and evaluate its correlation with clinicopathological parameters. METHODS: Serum DNA was extracted from the peripheral blood of 75 NSCLC patients and another 35 patients with benign pulmonary disease and 15 healthy donors. The methylation status of RASSF1A promoter was determined using methylation-specific PCR (MSP), and the correlation of methylation profiles with clinicopathological parameters was statistically analyzed. RESULTS: Aberrant methylation of RASSF1A was detected in 23 of 75 (30.7%) cancer patients, but in none of patients with benign pulmonary disease or in healthy donors (P <0.001). RASSF1A hypermethylation status was found to be correlated with late stage and poor differentiation (P < 0.05), but not with gender, age or histopathology in NSCLC patients. CONCLUSION: Hypermethylated RASSF1A promoter is frequently found in the serum DNA of non-small cell lung cancer patient, and RASSF1A may become a promising novel biomarker for diagnosis and prognosis prediction in lung cancer.

Detection of RASSF1A promoter hypermethylation in serum from gastric and colorectal adenocarcinoma patients.

AIM: To evaluate the diagnostic role of serum RASSF1A promoter hypermethylation in gastric and colorectal adenocarcinoma. METHODS: Methylation-specific polymerase chain reaction (MSPCR) was used to examine the promoter methylation status of the serum RASSF1A gene in 47 gastric adenocarcinoma patients, 45 colorectal adenocarcinoma patients, 60 patients with benign gastrointestinal disease (30 with benign gastric disease and 30 with benign colorectal disease), and 30 healthy donor controls. A paired study of RASSF1A promoter methylation status in primary tumor, adjacent normal tissue, and postoperative serum were conducted in 25 gastric and colorectal adenocarcinoma patients who later were underwent surgical therapy. RESULTS: The frequencies of detection of serum RASSF1A promoter hypermethylation in gastric (34.0%) and colorectal (28.9%) adenocarcinoma patients were significantly higher than those in patients with benign gastric (3.3%) or colorectal (6.7%) disease or in healthy donors (0%) (P < 0.01). The methylation status of RASSF1A promoter in serum samples was consistent with that in paired primary tumors, and the MSPCR results for RASSF1A promoter methylation status in paired preoperative samples were consistent with those in postoperative serum samples. The serum RASSF1A promoter hypermethylation did not correlate with patient sex, age, tumor differentiation grade, surgical therapy, or serum carcinoembryonic antigen level. Although the serum RASSF1A promoter hypermethylation frequency tended to be higher in patients with distant metastases, there was no correlation between methylation status and metastasis. CONCLUSION: Aberrant CpG island methylation within the promoter region of RASSF1A is a promising biomarker for gastric and colorectal cancer.

[Role of RASSF1A hypermethylation in prostate cancer].

RASSF1A gene cloned from 3p21.3 region is a novel candidate tumor suppressor gene. The aberrant methylation of CpG lands in the promoter region is the major inactivation mechanism of RASSF1A, and is significantly involved in the genesis and development of multiple solid tumors including prostate cancer. The methylation status examination of RASSF1A could serve as an important technique for the early diagnosis of prostate cancer, while methylation inhibitor is likely to become a novel therapeutic agent.