Integrative Cancer Therapies

Purpose: Essential thrombocythemia, polycythemia vera, and myelofibrosis are rare chronic hematological malignancies known as myeloproliferative neoplasms (MPNs) and are characterized by deregulated myeloid lineage cell production, splenomegaly, and heterogeneous symptom profiles. MPN patients suffer from a significant symptom burden (eg, fatigue, depressive symptoms, early satiety) and an impaired overall quality of life (QoL). Current treatments typically include pharmacological approaches, which may come with additional side effects and may be limited by treatment-associated toxicities (ie, cytopenias). Nonpharmacological approaches such as physical activity may be beneficial for reducing symptom burden and improving QoL. To date, no studies have examined physical activity as a nonpharmacological approach in MPN patients despite preliminary evidence supporting its benefit in other hematological cancers. The purpose of this article is to (1) review the literature related to physical activity and specific hematological cancer subtypes and to (2) make suggestions for future research involving physical activity in MPN patients as a symptom management strategy. Methods: A brief review of studies examining physical activity in leukemias, lymphomas, and myelomas (excluding stem-cell transplant patients) was conducted. Results: There is preliminary evidence to suggest that physical activity may be an effective approach to improve patient-reported outcomes (fatigue, depression, anxiety, sleep), physical fitness (cardiovascular fitness, balance, body composition), and overall QoL in other hematological cancers. Conclusions: Based on encouraging findings in other hematological cancers, future research should examine the feasibility and effectiveness of physical activity in MPN patients.

Artificial light at night (ALAN) for elongating photophase is a new source of pollution. We examined the association between measured ALAN levels and breast cancer (BC) standard morbidity ratio (SMR) at a statistical area (SA) level in an urban environment. Sample size consisted of 266 new BC cases ages 35-74. Light measurements (lux) were performed in 11 SAs. A new calculated variable of morbidity per SA size (SMR_35-74/km²) was correlated with the light variables per road length, using Pearson correlations (P < .05, 1-tailed). Looking for a light threshold, we correlated percentage of light points above SA light intensity median with SMR_35-74/km². SMR_35-74/km² was significantly and positively strongly correlated with mean, median, and standard-deviation (SD) light intensity per road length (r = .79, P < .01, R² = .63; r = .77, P < .01, R² = .59; and r = .79, P < .01, R² = .63). Light threshold results demonstrate a marginally significant positive moderate correlation between percentage of points above 16.3 lux and SMR_35-74/km² (r = .48, P < .07; R² = .23). In situ results support the hypothesis that outdoor ALAN illumination is associated with a higher BC-SMR in a specific area and age group. Moreover, we suggest an outdoor light threshold of approximately 16 lux as the minimal intensity to affect melatonin levels and BC morbidity. To the best of our knowledge, our attempt is the first to use this method and show such association between streetlight intensity and BC morbidity and therefore should be further developed.

Introduction: After allogeneic hematopoietic stem cell transplantation (HSCT), NK cell reconstitution, which is crucial for positive outcomes, is dominated by the CD56^bright subset with low NK cell cytotoxicity (NKCC) activity. Moderate exercise has been described as a potent NK cell stimulus in adults with cancer. Purpose: To determine the effects of a moderate-intensity exercise program on NK cell recovery early after HSCT and the feasibility of this intervention. Methods: Six children undergoing allogeneic HSCT were randomized to an exercise program (EP) or control (CT) group. The EP group performed a 10-week training combining in-hospital and home-based EP. Results: We observed a significant increase in the posttraining/pretraining ratio of the CD56^dim subset (EP = 1.27 ± 0.07; CT = 0.99 ± 0.08; P < .005) of the EP group. The ratio of NKCC was 8 times greater in the EP group. Conclusion: Data suggest that a moderate-intensity EP program performed early after HSCT is feasible and might redistribute the CD56^dim/CD56^brigh NK cell subset, improving NKCC. The results are still preliminary and must be interpreted with caution.

Background. Malignant pleural effusion (MPE) is a common complication in most malignancies. Despite its frequent occurrence, current knowledge of MPE remains limited and the effect of the management is still unsatisfying. Traditional Chinese medicine (TCM) external treatment has unique advantages, such as quicker efficacy and fewer side effects. Objective. To observe the effects and safety of Kang’ai Xiaoshui ointment (TCM herbal ointment) in MPE. Design. This was a placebo-controlled double-blinded randomized study. A total of 80 patients were enrolled, of which 72 were randomized to receive Kang’ai Xiaoshui ointment or placebo at an allocation ratio of 1:1. Kang’ai Xiaoshui ointment or placebo was applied on the thorax wall for 8 hours daily. The intervention lasted 2 weeks. Kang’ai Xiaoshui ointment consisted of Astragalus membranaces （黄芪）, Semen pharbitidis （牵牛子）, Cassia twig （桂枝）, Pericarpium arecae （大腹皮）, Curcuma zedoary （莪术）, Borneol （冰片), and other substances. In both groups, diuresis and drainages were used as needed. Outcomes covered the quantity of pleural effusion evaluation, TCM Symptom Scale, Karnofsky Performance Scale, and safety indicators such as routine blood test, blood biochemistry test, and response table of skin irritation. Results. Of 72 patients randomized to receive Kang’ai Xiaoshui ointment or placebo along with symptomatic treatment, the response rate was documented as 42.4% for the treatment group and 25.0% for the placebo group (P = .138). As for the TCM symptom scale, the treatment group showed improvement in chest distress (P = .003), fullness and distention (P = .042), shortness of breath (P < .001), no statistical significance in palpitation (P = .237), and pain (P = .063), whereas the placebo group did not show statistical significance in any of the 5 symptoms. Major adverse events related to the treatment, mainly skin irritation, were distributed equally. Conclusions. Kang’ai Xiaoshui ointment showed a potential of reducing MPE, and it could alleviate symptoms of dyspnea. Thus, it may be appropriate as a supplementary intervention for MPE. There were some flaws in the study design. A larger scale and better designed trial is advocated.

Purpose. So-called spontaneous remissions in cancer often seem to occur after febrile events. Mistletoe preparations (MPs) are used off-label intravenously to induce fever within concepts of integrative oncology. We wanted to investigate the frequency of febrile reactions and safety related to intravenously applied MPs (IAMPs). Methods. This was a retrospective analysis of data from consecutive cancer patients who were treated in 2 anthroposophic hospitals with IAMPs. The main outcome parameter was the rate of core temperature increase to ≥38.5°C within 24 hours after IAMPs. Secondary outcome parameters were Common Toxicity Criteria for Adverse Events (CTCAE; version 4.0). Results. 59 patients, with in total 567 IAMPs, were analyzed; 45 patients (76%, 95% CI = 65%-87%) had an increase of core temperature to ≥38.5°C after at least 1 treatment. Mean increase in temperature was 1.5°C ± 0.8°C. Adverse events were mostly fever-related symptoms (headache, joint pain, shivering). Grade 1 allergic reactions were documented in 0.6% of treatments. CTCAEs grade 3 to 5 did not occur; 38/59 patients had advanced and/or metastatic disease. Conclusion. IAMPs resulted in febrile reactions to >38.5°C in the majority of patients and can be considered as safe. Adverse events were mostly related to fever and were not severe.

Chronic inflammation may be a causative factor in breast cancer. One possible underlying mechanism is the generation of oxidative stress, which may favor tumorigenic processes. Antioxidant consumption may, therefore, help reduce tissue inflammation levels. However, few studies have explored this relation in breast tissue. We aimed to evaluate correlations between antioxidant (vitamin A/retinol, vitamin C, vitamin E, β-carotene, α-carotene, lycopene, lutein/zeaxanthin, β-cryptoxanthin, selenium, and zinc) intakes and protein expression levels of interleukin (IL)-6, tumor necrosis factor-α, C-reactive protein, cyclooxygenase-2, leptin, serum amyloid A1, signal transducer and activator of transcription 3, IL-8, IL-10, lactoferrin, and transforming growth factor-β measured in the normal breast tissue of 160 women diagnosed with breast cancer. Antioxidant intakes were collected using a self-administered food frequency questionnaire. Inflammation marker expression was assessed by immunohistochemistry. Correlations between antioxidant intakes and inflammatory marker expression were evaluated using Spearman’s partial correlation coefficients (r) for all women and for premenopausal and postmenopausal women separately. After Bonferroni correction, negative correlations were observed between dietary β-tocopherol and IL-10 expression in all women combined (r = −0.26, P = .003) and among postmenopausal women (r = −0.39, P = .003). For all women, a negative correlation was found between total zinc intakes and IL-10 (r = −0.26, P = .002). Among postmenopausal women, dietary selenium intake was negatively correlated with the expression of lactoferrin (r = −0.39, P = .003). No associations were observed in premenopausal women. Our findings suggest that consumption of specific antioxidants, including β-tocopherol, zinc, and selenium, may act on the breast tissue through mechanisms affecting the expression of some inflammation markers, particularly among postmenopausal women.

Docetaxel (DTX) is an effective commercial anticancer agent for chemotherapy in non–small cell lung cancer (NSCLC), breast cancer, gastric cancer, and prostate cancer, but its adverse effects including edema, neurotoxicity, and hair loss limit its application. To improve the chemotherapeutic efficacy of DTX and reduce adverse effects, combination therapy is one of the alternative methods. So chrysin, which has various biological activities including anticancer effects, was considered. In vitro, the combination of chrysin and DTX was investigated in A549 cells. Increased cytotoxicity, suppressed cellular proliferation, and induced apoptosis were observed with posttreatment of chrysin following DTX treatment. In vivo, chrysin enhanced the tumor growth delay of DTX and increased DTX-induced apoptosis in the A549-derived xenograft model. Furthermore, chrysin prevented DTX-induced edema in ICR mouse. These results indicated that chrysin strengthened the therapeutic efficacy of DTX and diminished the adverse effect of DTX, suggesting chrysin could be exploited as an adjuvant therapy for NSCLC.

Background. Phyllanthus emblica L (PEL), a well-known medical plant, has been used in Asian countries for a long time. Increasing evidence suggests that it can prevent the tumorigenesis of cancer associated with nonresolving inflammation. However, the possible anti-inflammatory mechanism responsible for preventing tumorigenesis of precancerous lung lesions is not well elucidated. Materials and methods. Male A/J mice were randomly divided into 5 groups with 10 mice in each group: (1) blank group (saline), (2) benzo(a)pyrene [B(a)P] group, (3) and (4) B(a)P + PEL (5 g/kg/d, 10 g/kg/d, administered by gavage), (5) B(a)P + celecoxib (30 mg/kg/d, administered by gavage). Nodes on the lung surface were observed and calculated. The levels of macrophage inflammatory protein (MIP-2), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β were detected by enzyme-linked immunosorbent assay (ELISA) kits. Cyclo-oxygenase-2 (COX-2), hypoxia-inducible factor-1 (HIF-α), IL-1β, miR-101, and Lin28B protein levels were evaluated by immunohistochemistry and Western blotting. Results. PEL extract treatment significantly reduced the number of nodes on the lung surface and attenuated B(a)P-induced levels of proinflammatory cytokines MIP-2, TNF-α, IL-6, and IL-1β in lung tissue. The protein expressions of COX-2 and HIF-α were significantly decreased by the treatment of PEL. In addition, both PEL extract and celecoxib markedly upregulate the expression of miR-101 while downregulating IL-1β and Lin28B levels. Conclusion. Our study indicated that treatment with PEL extract can not only protect the lung from inflammatory injury but effectively prevent precancerous lung lesions through regulating the IL-1β/miR-i101/Lin28B signaling pathway.

JC-001 is a Chinese medicine that has been used to treat liver disease; however, its significance in cancer treatment has not been characterized. In this study, we used an immunocompetent tumor model to characterize the antitumor activity of JC-001. A total of 48 Hepa 1-6 tumor-bearing C57BL/6 mice were randomly grouped into 4 groups and treated with H₂O or JC-001 via oral administration. After hepatoma cell lines, including HepG2, Hep3B, SK-Hep-1, and Hepa 1-6, underwent 96 hours of JC-001 treatment, a low cytotoxic effect was observed. In contrast, no direct cytotoxic effect of JC-001 on a normal human liver cell line, THLE-3, was observed under the same incubation conditions. Using a murine tumor model, we found that tumor growth could be inhibited by JC-001 in C57BL/6 mice but not in immunodeficient mice. Histopathological analysis of tumors from C57BL/6 mice revealed immune cell infiltration in tumors from the JC-001–treated group, as observed by hematoxylin and eosin staining; in addition, Ki67, hypoxia-inducible factor-1-α, and high mobility group box 1 expression levels were suppressed in the tumors. Both the coculture assay and murine spleen mRNA quantitative PCR analyses demonstrated that JC-001 could suppress Th17 immunity. Our data suggest that JC-001 is a Chinese medicine with low cytotoxicity that can significantly suppress tumor growth by immune regulation. This herbal remedy has great potential for future clinical application in hepatoma therapy.

The BCR-ABL kinase inhibitor, imatinib mesylate, is the front-line treatment for chronic myeloid leukemia, but the emergence of imatinib resistance has led to the search for alternative drug treatments. There is a pressing need, therefore, to develop and test novel drugs. Natural products including plants, microorganisms, and halobios provide rich resources for discovery of anticancer drugs. In this article, we demonstrate that emodin inhibited the growth of K562 cells harboring BCR-ABL in vitro and in vivo, and induced abundant apoptosis, which was correlated with the inhibition of PETN/PI3K/Akt level and deletion of BCR-ABL. These findings suggest that emodin is a promising agent to kill K562 cells harboring BCR-ABL.

Although it may sound unpleasant, camel urine has been consumed extensively for years in the Middle East as it is believed to be able to treat a wide range of diseases such as fever, cold, or even cancer. People usually take it by mixing small drops with camel milk or take it directly. The project aims to study the effects of camel urine in inhibiting the growth potential and metastatic ability of 4T1 cancer cell line in vitro and in vivo. Based on the MTT result, the cytotoxicity of camel urine against 4T1 cell was established, and it was dose-dependent. Additionally, the antimetastatic potential of camel urine was tested by running several assays such as scratch assay, migration and invasion assay, and mouse aortic ring assay with promising results in the ability of camel urine to inhibit metastatic process of the 4T1 cells. In order to fully establish camel urine’s potential, an in vivo study was carried out by treating mice inoculated with 4T1 cells with 2 different doses of camel urine. By the end of the treatment period, the tumor in both treated groups had reduced in size as compared to the control group. Additional assays such as the TUNEL assay, immunophenotyping, cytokine level detection assay, clonogenic assay, and proteome profiler demonstrated the capability of camel urine to reduce and inhibit the metastatic potential of 4T1 cells in vivo. To sum up, further study of anticancer properties of camel urine is justified, as evidenced through the in vitro and in vivo studies carried out. Better results were obtained at higher concentration of camel urine used in vivo. Apart from that, this project has laid out the mechanisms employed by the substance to inhibit the growth and the metastatic process of the 4T1 cell.

Most of the present anticancer drugs are highly cytotoxic and focus mainly on killing tumor cells rather than slowing the progress of cancer metastasis. Evidence has been reported that bridges the mechanisms of inflammation and tumor invasion. Therefore, we evaluated the potency in cancer metastasis chemoprevention of compounds and a coumarin extracted from Murraya exotica, which is known for its anti-inflammation bioactivity. By carrying out experiments in vitro, we found the root extracts more efficient than the leaf extracts in restraining cell migration of MDA-MB-231 cells, while leaf extracts presented slightly stronger inhibition of tumor cell adhesion at low concentrations. In addition, compared to root extracts, a novel coumarin identified previously from root extracts showed equal inhibition on cancer cell adhesion and less inhibition on cell migration. All extracts used in this study presented low cytotoxicity in vitro. Through comparison of the contents of leaf and root extracts from M exotica, several compounds are considered promising against cancer metastasis. This study evaluates the worth of further development of M exotica to find its effect on cancer metastasis chemoprevention.

Background. Murraya koenigii (L.) Spreng, is a significant herb of traditional Ayurvedic system of medicine. Koenimbine, a carbazole alkaloid isolated from this plant holds antiproliferative and apoptotic effects. The aim of this study was to assess koenimbine-induced DNA damage and to clarify the role of free radicals in cell death mechanisms, using HepG2 cells. Methods. The level of cytotoxicity was assayed by MTT assay. To elucidate the role of glutathione (GSH), the intracellular GSH level was analyzed. The effect of koenimbine in the cell mitochondria was evaluated using mitochondrial membrane potential (MMP) changes. Single cell gel electrophoresis assay was used to examine the level of DNA damage. Heat shock proteins, Hsp 70 and Hsp 90 expressions were checked at mRNA and protein level. Ascorbic acid and catalase were used as control antioxidants. Results. It was observed that koenimbine considerably increased DNA damage in HepG2 cells at subcytotoxic concentrations. Koenimbine induced the increased levels of reactive oxygen species (ROS) and reduction of GSH level in HepG2 cells, together with time-dependent loss of MMP. In addition, results clearly showed that koenimbine encouraged cells to express Hsp 70 and Hsp 90 in a concentration-dependent manner up to a concentration of 100 µM and a time-dependent manner at 24-hour incubation both at transcriptional and translational levels. The antioxidant capacity of ascorbic acid was found to be not as prominent as to catalase throughout the study. Conclusion. Based on these data it can be concluded that koenimbine causes DNA strand breaks in HepG2 cells, probably through oxidative stress. Moreover, the oxidative stress induced was closely associated with MMP reduction and GSH depletion associated with HSP modulation at subcytotoxic concentration.

Objectives: To evaluate potential hepatic metabolism-mediated drug interactions with fucoidan from Undaria pinnatifida (UPF) or Fucus vesiculosus (FVF) and potential growth inhibition activity with either fucoidan alone or with chemotherapy. In vivo studies were done to confirm safety and investigate fucoidan-mediated immune modulation. Methods: Cytochrome P450 (CYP450) 3A4, 2C8, 2C9, and 2D6 inhibition experiments were conducted in vitro followed by an ex vivo human hepatocytes model to evaluate the CYP450 induction potential of each fucoidan at highest theoretical concentrations. Four hepatic metabolism phase II pathways—glutathione S transferase (GST), quinone oxidoreductase (QOR), catechol-O-methyltransferases (COMT), and uridine di-phosphate (UDP)-glucuronosyltransferase (UGT)—were evaluated with validated immunoassays. Growth inhibition assays were performed with each fucoidan alone and in combination with chemotherapy agents in a panel of human cancer cell lines. In vivo studies evaluated safety and immune modualtion. Results: CYP450 inhibition was observed with FVF. The GST, QOR, and UGT pathways had no changes. UPF and FVF both interacted with COMT. No growth inhibitory activity in cancer cell lines was observed. UPF and FVF had synergistic activity with paclitaxel or tamoxifen and additive activity with topotecan. In vivo, FVF decreased HeLa human cervical tumor growth and both FVF and UPF decreased TOV-112D human ovarian tumor growth. Otherwise, no significant change in tumor growth was observed. FVF immune modulation of IgG and IL-6 was observed (p<0.03). Conclusion: At higher doses, UPF and FVF may have limited potential for drug-supplement interactions, with either CYP450 or COMT hepatic metabolism pathways. Additional studies are warranted to evaluate to confirm findings of fucoidans in combination with chemotherapy.

Background: β-Lapachone is a quinone-containing compound found in red lapacho (Tabebuia impetiginosa, syn. T avellanedae) trees. Lapacho has been used in traditional medicine by several South and Central American indigenous people to treat various types of cancer. The purpose of this study was to investigate the antimetastatic properties of β-lapachone and the underlying mechanisms using colon cancer cells. Methods: This research used metastatic murine colon cancer cell lines, colon 26 (CT26) and colon 38 (MC38). A WST assay, annexin V assay, cell cycle analysis, wound healing assay, invasion assay, western blot analysis, and real-time reverse transcription–polymerase chain reaction were performed to examine the effects of β-lapachone on metastatic phenotypes and molecular mechanisms. The effect of β-lapachone on lung metastasis was assessed in a mouse experimental metastasis model. Results: We found that the inhibition of proliferation of the colon cancer cell lines by β-lapachone was due to the induction of apoptosis and cell cycle arrest. β-Lapachone induced the apoptosis of CT26 cells through caspase-3, -8, and -9 activation; poly(ADP-ribose) polymerase cleavage; and downregulation of the Bcl-2 family in a dose- and time-dependent manner. In addition, a low concentration of β-lapachone decreased the cell migration and invasion by decreasing the expression of matrix metalloproteinases-2 and -9, and increased the expression of tissue inhibitors of metalloproteinases-1 and -2. Moreover, β-lapachone treatment regulated the expression of epithelial-mesenchymal transition markers such as E- and N-cadherin, vimentin, β-catenin, and Snail in CT26 cells. In the mouse experimental metastasis model, β-lapachone significantly inhibited the lung metastasis of CT26 cells. Conclusions: Our results demonstrated the inhibitory effect of β-lapachone on colorectal lung metastasis. This compound may be useful for developing therapeutic agents to treat metastatic cancer.

Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. Although surgery is known as the most promising radical treatment, a high recurrent or metastatic rate after surgery has limited its clinical efficacy. Sorafenib, a target agent, has seemed to be the only option for metastatic HCC patients to date, but none of clinical trials showed it could prolong the overall survival (OS) of advanced HCC to 1 year. How to prolong the OS and improve cure rate of HCC patients is still beset with difficulties. This report presents a rare case of recurrent HCC patient with complete regression of target lesion with 2 years of Chinese herbal treatment. A 64-year-old Chinese man with hepatitis B virus–associated chronic hepatitis presented HCC has been clinically diagnosed tumor relapse and omentum metastasis with computed tomography and α-fetoprotein blood test 4 months after surgery. It was decided the patient would receive traditional Chinese medicine treatment because of poor prognosis. After approximately 2 years of treatment, recurrent hepatic tumor and omentum metastasis have been found in complete regression. The patient remains alive over 31 months after relapse.

A 52-year-old Hispanic male presented with hematuria and was later diagnosed with a large invasive high-grade urothelial cell carcinoma (UCC) of the urinary bladder, but with ambiguous pT1/pT2 staging regarding musclaris propria invasion by UCC. The conventional treatment including radical cystoprostatectomy followed by neoadjuvant chemotherapy with or without radiation therapy was presented. The patient decided to delay the standard therapy until a later stage, but elected to go through transurethral resection of bladder tumor (TURBT) without Bacillus Calmette-Guérin instillation. Following TURBT, the patient started oral Boswellia sacra gum resin (aka frankincense or Ru Xiang in Chinese) hydrodistillates (BSGRH) administration at 3 mL daily with lifestyle changes, and continued this regimen in the last 25 months. Within the first year after diagnosis, the patient experienced 2 recurrences. Recurrent tumors were removed by TURBT alone and both tumors were far smaller than the original one. After the second recurrence, the patient has no detectible cancer in the bladder based on cystoscopy for 14 months and has an intact genitourinary system. His liver and kidney functions are considered to be normal based on blood chemistry tests. This index case suggests that BSGRH may have cancer chemopreventive effects on UCC. The use of Boswellia-derived products in the management of cancer has been well document in other published studies, and boswellic acids have been suggested to be the major component. However, BSGRH contains very little boswellic acids. Demonstration of cancer chemoprevention using BSGRH is one step forward in isolating the key components other than boswellic acids in frankincense. The critical question as to whether these components can simultaneously activate multiple pathways in cancer cells to execute cancer suppression/cytotoxicity or prevention effects remains to be addressed. More studies including identification of key molecules, pharmacokinetics of major compounds, as well as long-term benefits and possible adverse effects will be needed to meet the guidelines of the US Food and Drug Administration for botanical drug development.