Diterpene promptly executes a non-canonical autophagic cell death in doxorubicin-resistant lung cancer.

16-hydroxycleroda-3,13-dien-15,16-olide (HCD) has antitumor activity reported in numerous types of cancers. However, the efficacy of HCD treatment in non-small-cell lung cancer (NSCLC) cells and doxorubicin-resistant (Dox-R)-NSCLC cells remains to be unraveled. The underlying anti-cancer mechanism of HCD on Dox-R and Dox-sensitive (Dox-S) of A549 cells was also investigated. Cytotoxicity of HCD against two cell lines (Dox-S and Dox-R) were determined via MTT assay, flow cytometry, and Western blot. A further examination of its anti-cancer efficacy was performed in A549-bearing xenograft mice via orthotopic intratrachea (IT) inoculation, which showed that HCD could arrest both Dox-S and Dox-R cells at G2/M phase without altering the sub-G1 cycle along with increasing of cleaved-PARP. HCD downregulated the mTOR/Akt/PI3K-p85 and PI3K-ClassIII/Beclin-1 signals and upregulated p62/LC3-I/II expressions to further confirm that the cell autophagy of NSCLC cells after being HCD-induced. Morphological observations of mouse lung sections illustrated that fewer cancer cells accumulated close to the trachea while less neoplastic activities were found in HCD orthotopic treated mice without liver, kidney, and spleen toxicity. Lastly, Dox, HCD, and target therapy medicines of EGFR and ALK were nicely docked with EGFR, ALK, and mTOR. Conclusively, HCD was demonstrated the chemotherapeutic potential regardless of Dox-R and Dox-S cells, suggesting natural autophagic inducer HCD provides a promising lead compound for new drug discovery and development of lung cancer therapies.

Ovatodiolide suppresses nasopharyngeal cancer by targeting stem cell-like population, inducing apoptosis, inhibiting EMT and dysregulating JAK/STAT signaling pathway.

BACKGROUND: Treatment for metastatic nasopharyngeal carcinoma (NPC) is challenging. Till now, a truly effective chemotherapy regimen for NPC has not yet been identified. These clinical observations prompted us to investigate a potential drug as alternative option for treating. PURPOSE: This study evaluated the inhibitory effects of Ovatodiolide (Ova), on tumorigenic and cancer stem cell characteristics of NPC cells. METHODS: Two NPC cell lines (NPC-BM1 and NPC-BM2) were used to examine the anticancer effects of Ova and the molecular mechanism underlying these activities by using sulforhodamine B cytotoxicity assay, western blot, immunofluorescence, migration, colony and tumorsphere formation assays. RESULTS: Ova significantly inhibited the viability of BM1 and BM2 cells, downregulated Bcl-xL and Puma, and upregulated Bax/Bad expression levels. Ova dose-dependent suppressed migratory/invasive potential of NPC cells, and reduced ability to form colonies. Ova-induced apoptosis correlated with increased Bax/Bcl-xL ratio while NPC motility and colony formation inhibition were associated with reduced expression of p-FAK, p-PXN, F-actin, and Slug proteins and increased E-cadherin. Furthermore, ova inhibited NPC tumorsphere formation, associated with decreased SOX2, OCT4 and JAK-STAT signaling pathway. Ova also attenuated NPC stem cell tumorigenicity, inhibited tumor growth, and enhanced the sensitivity of NPC cells to cisplatin treatment, in vivo. CONCLUSIONS: Our results demonstrated the anticancer efficacy of Ova in NPC and its potential as a putative inhibitor of JAK2 and STAT3, which are essential in tumorigenesis of NPC. Further development of Ova is encouraged.

Investigation of ovatodiolide, a macrocyclic diterpenoid, as a potential inhibitor of oral cancer stem-like cells properties via the inhibition of the JAK2/STAT3/JARID1B signal circuit.

BACKGROUND: The cancer stem cells (CSCs) have been shown to play key roles in the oral cancer initiation, distant metastasis, the development of chemoresistance and recurrence after treatment. Therefore, the inhibition of oral CSCs has been the target for therapeutic development. PURPOSE: In this study, we investigated the anti-CSCs potential of Ovatodiolide (Ova), a diterpenoid isolate of Anisomeles indica, in vitro and in vivo. METHODS: Oral CSCs were treated with Ova, and the expression of pluripotency factors Oct4, Sox-2, and Nanog were evaluated by western blot. Effect of Ova on self-renewal capacity and clonogenicity were assessed with the sphere formation and clonogenic assay in CSCs model derived from oral cancer cell. The effect of Ova was also investigated in a mouse xenograft model obtained by injecting nude mice with oral CSCs cells. RESULTS: We demonstrated that Ova significantly and dose-dependently suppressed oral cancer cell viability and colony formation; Ova markedly inhibited the ALDH1 activities and reduced the CD44high/ALDHrich cell sub-population. Additionally, Ova suppressed orosphere formation by down-regulating CD133, Klf4, Oct4A, Nanog and JARID1B expression. Furthermore, Ova-mediated anti-cancer effects were associated with the dose-dependent reduction in the expression levels of STAT3, p-STAT3, pJAK2, pAKT and pERK1/2 protein. Moreover, Ova synergistically enhanced the anticancer effect of cisplatin against the SAS, FaDu, HSC-3 and TW2.6 orospheres. Ova significantly attenuated the tumor-initiating potential of orosphere in mouse xegnograft model. CONCLUSION: These results demonstrate that Ova effectively suppressed oral tumorigenesis and stemness properties via JAK2/STAT3 signaling. Ova may be considered for future clinical usage.

Rhodiola crenulata Attenuates γ-Ray Induced Cellular Injury via Modulation of Oxidative Stress in Human Skin Cells.

Skin injury is a major complication during radiation therapy and is associated with oxidative damage to skin cells. An effective and safe radioprotectant to prevent this skin damage is still unavailable. The Rhodiola crenulata root extract (RCE) has been reported to be a free radical scavenger and a potent anti-oxidant in both in vitro and in vivo models. In the current study, we investigated the effects of RCE on ionizing radiation-induced skin injury and its underlying mechanisms. HaCaT cells - a non-cancerous skin cell line together with HepG2, Caco2, A549, and OECM cancer cell lines - were pre-treated with RCE for 24[Formula: see text]h followed by exposure to 15 Gy using Caesium-137 as a γ-ray source. The cell viability was measured. In HaCaT cells, oxidative stress markers, cellular apoptosis pathways, matrix metalloproteinases (MMPs), and pro-inflammatory cytokine gene expression were studied. We found that RCE significantly protected HaCaT cells, but not cancer cells from the loss of viability induced by exposure to ionizing radiation. RCE attenuated radiation-induced oxidative stress markers, cell apoptosis, MMP levels, and expression of cytokine genes. RCE also limited the induction of p53 and p21 by radiation exposure. These findings indicate that RCE may selectively protect the skin cells from ionizing radiation without altering its ability to kill cancer cells. Therefore, we suggest that RCE or its derivatives could serve as a novel radioprotective therapy.

Danshen extract circumvents drug resistance and represses cell growth in human oral cancer cells.

BACKGROUND: Danshen is a common traditional Chinese medicine used to treat neoplastic and chronic inflammatory diseases in China. However, the effects of Danshen on human oral cancer cells remain relatively unknown. This study investigated the antiproliferative effects of a Danshen extract on human oral cancer SAS, SCC25, OEC-M1, and KB drug-resistant cell lines and elucidated the possible underlying mechanism. METHODS: We investigated the anticancer potential of the Danshen extract in human oral cancer cell lines and an in vivo oral cancer xenograft mouse model. The expression of apoptosis-related molecules was evaluated through Western blotting, and the concentration of in vivo apoptotic markers was measured using immunohistochemical staining. The antitumor effects of 5-fluorouracil and the Danshen extract were compared. RESULTS: Cell proliferation assays revealed that the Danshen extract strongly inhibited oral cancer cell proliferation. Cell morphology studies revealed that the Danshen extract inhibited the growth of SAS, SCC25, and OEC-M1 cells by inducing apoptosis. The Flow cytometric analysis indicated that the Danshen extract induced cell cycle G0/G1 arrest. Immunoblotting analysis for the expression of active caspase-3 and X-linked inhibitor of apoptosis protein indicated that Danshen extract-induced apoptosis in human oral cancer SAS cells was mediated through the caspase pathway. Moreover, the Danshen extract significantly inhibited growth in the SAS xenograft mouse model. Furthermore, the Danshen extract circumvented drug resistance in KB drug-resistant oral cancer cells. CONCLUSION: The study results suggest that the Danshen extract could be a potential anticancer agent in oral cancer treatment.

Comparison Between Child-Turcotte-Pugh and Albumin-Bilirubin Scores in Assessing the Prognosis of Hepatocellular Carcinoma After Stereotactic Ablative Radiation Therapy.

PURPOSE: To evaluate the prognostic performance of the Child-Turcotte-Pugh (CTP) score and the albumin-bilirubin (ALBI) score in hepatocellular carcinoma (HCC) patients treated using stereotactic ablative radiation therapy (SABR). METHODS AND MATERIALS: This retrospective study evaluated the data of patients with HCC who underwent SABR between December 2007 and June 2015. We collected pretreatment CTP and ALBI scores and analyzed their correlation with survival and liver toxicity. RESULTS: This study included 152 HCC patients: 78.3% of CTP class A and 21.7% of CTP class B. The median ALBI score was -2.49 (range, -3.67 to -0.84) with 39.5% of grade 1, 56.6% of grade 2, and 3.9% of grade 3. The CTP classification and ALBI grade were significantly associated with overall survival (P<.001). Albumin-bilirubin grade (1 vs 2) had a trend to stratify CTP class A patients into 2 risk groups of mortality (P=.061). Combined CTP class and ALBI score could predict development of radiation-induced liver disease (2.4% in CTP A-ALBI < -2.76, 15.1% in CTP A-ALBI ≥ -2.76, and 25.8% in CTP B). CONCLUSION: Albumin-bilirubin score is a potential predictor for both survival and liver toxicity. Complementary use of CTP and ALBI score could predict the risk of post-SABR liver toxicity. Further prospective studies are necessary before use of the ALBI score can become part of daily practice.

Lapatinib and platinum-based chemotherapy ameliorate breast cancer with choroidal metastasis and restore visual acuity.

Involvement of the central nervous system in metastatic breast cancer is a particularly dismal occurrence because of its effects on mortality and quality of life. Development of choroidal metastasis in a breast cancer patient indicates poor prognosis and has become the major life-limiting problem. Various treatment modalities for choroidal metastasis have been applied with different efficacy. Here we describe a patient with HER2-overexpressing breast cancer and limited choroidal metastasis who responded to an HER2 tyrosine kinase inhibitor after failure of radiotherapy and chemotherapy. Her visual acuity was completely and durably restored after the targeted therapy. This case provides a unique treatment experience of breast cancer with choroidal metastasis.

Hyperbaric oxygen therapy for late radiation-associated tissue necroses: is it safe in patients with locoregionally recurrent and then successfully salvaged head-and-neck cancers?

PURPOSE: To test, in a retrospective matched-pair study, whether necrosis-rescuing hyperbaric oxygen therapy (HBOT) increases the risk of cancer re-recurrence in patients with locoregionally recurrent and then successfully salvaged head-and-neck cancers. METHODS AND MATERIALS: Between January 1995 and July 2004, we retrospectively identified 22 patients with locoregionally recurrent and then successfully salvaged head-and-neck cancers. We defined two groups: the HBOT group, 11 patients with HBOT for rescuing late radiation-associated tissue necroses; and the non-HBOT group, the other 11 matched-pair patients without HBOT. Between the two groups, the following four factors were matched for case pairing: primary cancer subsite, initial cancer stage, age, and gender. RESULTS: Three findings indicate that HBOT increases the risk of cancer re-recurrence. First, we observed more cancer re-recurrences in the HBOT group than in the non-HBOT group: 9 of 11 vs. 4 of 11, with 5-year disease-free survival rates after salvage of 32.7% vs. 70.0% (hazard ratio 3.2; 95% confidence interval 1.03-10.7; p = 0.048). Second, re-recurrences developed rapidly after HBOT in 6 patients. Third, 3 patients had unusual cancer re-recurrences after HBOT. Remarkably, of 9 patients with cancer re-recurrences in the HBOT group, 4 patients had cancer disease-free intervals of 9 months or less before HBOT. CONCLUSIONS: Necrosis-rescuing HBOT should be given with caution in patients with locoregionally recurrent and then successfully salvaged head-and-neck cancers; if it cannot be omitted entirely, deferring HBOT 9 months or longer after cancer re-treatment may be prudent.