Integration of phytotherapy and chemotherapy: Recent advances in anticancer molecular pathways.

Cancer is a disease characterized by abnormal and uncontrolled growth of cells, leading to invasion and metastasis to other tissues. Chemotherapy drugs are some of the primary treatments for cancer, which could detrimentally affect the cancer cells by various molecular mechanisms like apoptosis and cell cycle arrest. These treatment lines have always aligned with side effects and drug resistance. Due to their anticancer effects, medicinal herbs and their active derivative compounds are being profoundly used as complementary treatments for cancer. Many studies have shown that herbal ingredients exert antitumor activities and immune-modulation effects and have fewer side effects. On the other hand, combining phytotherapy and chemotherapy, with their synergistic effects, has gained much attention across the medical community. This review article discussed the therapeutic effects of essential herbal active ingredients combined with chemotherapeutic drugs in cancer therapy. To write this article, PubMed and Scopus database were searched with the keywords "Cancer," "Combination," "Herbal," "Traditional," and "Natural." After applying inclusion/exclusion criteria, 110 articles were considered. The study shows the anticancer effects of the active herbal ingredients by inducing apoptosis and cell cycle arrest in cancer cells, especially with a chemotherapeutic agent. This study also indicates that herbal compounds can reduce side effects and dosage, potentiate anticancer responses, and sensitize cancer cells to chemotherapy drugs.

Chamomile and Urtica dioica extracts improve immunological and histological alterations associated with polycystic ovarian syndrome in DHEA -induced mice.

BACKGROUND: One of the novel mechanisms in the pathogenesis of Polycystic ovary syndrome (PCOS) is low-grade chronic inflammation. Chamomile (Matricaria recutita L.) and Nettle (Urtica dioica), with phytoestrogenic and antioxidant properties, are traditionally used to treat gynecological diseases. This study investigated the immune-modulating effects of these two plants. METHODS: Following the induction of PCOS by subcutaneous injection (SC) of Dehydroepiandrosterone (DHEA) in BALB / C mice. Mice were treated in five groups: Sham, PCOS, PCOS + Chamomile, PCOS + Nettle, and PCOS + Chamomile and Nettle for 21 days. Ovarian morphology, blood antioxidant capacity, the abundance of Treg cells, and expression of matrix metalloproteinase-9 (MMP-9), transforming growth factor-ß (TGF-ß), cyclooxygenase-2 genes (COX-2), and tumor necrosis factor-alpha (TNF-α) were measured. RESULTS: Folliculogenesis, Cystic follicles, and corpus luteum improved in the treatment groups (P < 0. 05). Treg cells in the DHEA group were significantly reduced compared to the Sham group (P < 0. 01). However, this decrease was not corrected in treatment groups (P > 0. 05). Total serum antioxidant capacity was significantly increased in the treatment group of Nettle and Chamomile + Nettle (P < 0. 05). The expression of MMP9 and TGFß genes in the PCOS group was significantly higher than the Sham group (P < 0. 05), which the expression of MMP9 was corrected by treatment with Chamomile + Nettle extract (P < 0. 05). CONCLUSION: Chamomile and Nettle extract may be an effective supplement in improving the histological and immunological changes of PCOS. However, more research is needed to confirm its effectiveness in humans.

Synergistic apoptotic effects of ethanolic extracts of ginger and Ganoderma lucidum in a colorectal cancer cell line.

Current conventional therapy for colorectal cancer includes surgery, radiation and chemotherapy, all of which produce side effects. Herbal medicine can control the side effects of conventional treatments. We investigated the synergistic effect of a mixture of Zingiber officinale Roscoe (Ginger) and Ganoderma lucidum extracts on colorectal cancer cell apoptosis in vitro. We prepared ethanolic extracts of ginger (GEE) and G. lucidum (GLEE). Cytotoxicity was evaluated using MTT assay and the half-maximal inhibitory concentration (IC50) of each extract was calculated. The effect of these extracts on apoptosis in cancer cells was assessed using flow cytometry; Bax, Bcl2 and caspase-3 gene expression was evaluated using real-time PCR. GEE and GLEE decreased CT-26 cell viability significantly in a dose-dependent manner; however, the combined application of GEE + GLEE was most effective. Bax:Bcl-2 gene expression ratio, caspase-3 gene expression and the number of apoptotic cells were increased significantly in CT-26 cells treated at the IC50 level of each compound, especially in the GEE + GLEE treatment group. Combined ginger and Ganoderma lucidum extracts exhibited synergistic antiproliferative and apoptotic effects on colorectal cancer cells.

Macrophage polarization by phytotherapy in the tumor microenvironment.

Several signaling pathways were involved in M1 (classic) and M2 (alternative) macrophage polarization. Disruption of M2-related signaling pathways and improvement of M1-related signaling pathways can be identified as one of the cancer therapeutic approaches. Prevention of macrophage differentiation into M2 by different herbal agents with antitumor properties can be considered as a promising therapeutic target for cancer patients. In the present review study, we investigated the effect of herbal compounds on M1 and M2 related signaling pathways to reduce M2 and increase M1 macrophage polarization for the treatment of different types of cancer.

Synergistic Evaluation of Ginger and Licorice Extracts in a Mouse Model of Colorectal Cancer.

Herbal medicine can be used to overcome the side effects of conventional treatments. This study aimed to evaluate the anticancer activities of ginger and licorice extracts, as well as the synergistic effects of their combination. Ginger ethanolic extract (GEE) and licorice methanolic extract (LME) were isolated by a Soxhlet extractor. Next, the anti-proliferative activity of the extracts, apoptosis induction, tumor growth inhibition, and tumor-infiltrating T lymphocytes were investigated. The MTT (3-[4, 5-dimethylthiazol-2-yl]-2, five diphenyl tetrazolium bromide) assay showed that GEE and LME decreased the CT26 cell viability in a dose-dependent manner; however, the GEE + LME combination was more effective (P < 0.05). The CT26 cells treated with each extract showed a significant increase in Bax/Bcl-2 ratio and caspase-3 gene expression, especially in the GEE + LME group (P < 0.001). Tumor volume significantly reduced in the GEE + LME group, compared to the negative controls. Finally, mice treated with GEE + LME showed a significant increase in the CTL/Treg cell ratio (P < 0.001) and Bax/Bcl2 ratio (P < 0.05). The study results revealed that GEE + LME can suppress cancer cell growth, increase apoptosis, and improve CTL infiltrating to the tumor site in a synergetic manner in-vivo and in-vitro. Therefore, the prepared mixture can be used in future clinical trials.

Combination therapy with interferon beta-1a and sesame oil in multiple sclerosis.

OBJECTIVES: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. Several effector mechanisms are involved in the immunopathology of MS and a variety of medications such as beta interferons are applied to treat the disease. This study was conducted to evaluate the anti-inflammatory and immunomodulatory effects of sesame oil in combination with interferon beta-1a in MS treatment. METHODS: Ninety-three MS patients were enrolled in the study. The patients were randomly divided into two groups. The control group (n = 39) received 30 µg/week of interferon beta-1a intra-muscularly. The sesame oil-treated group (n = 54) received interferon beta-1a the same as the control group with the addition of 0.5 ml/kg/day of oral sesame oil for 6 months. RESULTS: After the 6-month study period, the interleukin (IL)-10 concentration in the sesame oil-treated group was significantly greater than that of the control group (p = 0.04). The concentrations of interferon-γ (IFN-γ), nitric oxide (NO), and tumor necrosis factor-α (TNF-α) in the sesame oil group after treatment were significantly less than those of the control group (p = 0.029, p = 0.0001, and p = 0.01, respectively). Lymphocyte proliferation in the sesame oil-treated group was significantly lower at the end of the study than at the beginning (p = 0.001). CONCLUSION: Sesame oil, through a decrease in IFN-γ secretion and anti-inflammatory and anti-oxidant activities, may have beneficial effects for MS patients.

Therapeutic effects of walnut oil on the animal model of multiple sclerosis.

OBJECTIVES: Therapeutic approaches for multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), are accompanied by various undesirable side effects. Owing to the anti-inflammatory and antioxidant effects of walnut, we investigated its effects on the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. METHODS: After EAE induction in mice, the treated group was gavaged daily with walnut oil. The weights and clinical symptoms were monitored daily for 21 days following the onset of symptoms. The spleens and brains of the mouse were removed and used for ELISA and histological studies. RESULTS: The average disease severity and plaque formation in the brains of the walnut oil-treated group were significantly lower (P < 0.05) than those of the untreated group. Stimulated splenocytes of the treated group expressed significantly less INF-γ and interleukin (IL)-17 than the untreated group with no significant differences in IL-10 or IL-5 production. In serum from the treated group, IL-17 expression was also significantly less than in the untreated group, while IL-10 was greater (P < 0.05). CONCLUSION: Walnut oil significantly reduced disease severity, inhibited plaque formation, and altered cytokine production. More studies are required to identify the mechanism of action of walnut oil as a valuable supplement in the treatment of MS.

Serum markers of inflammation and oxidative stress in chronic opium (Taryak) smokers.

A relationship between the expression of inflammation markers, oxidative stress and opium use has not been clearly established. This study was done to determine serum high-sensitivity C-reactive protein (hs-CRP), quantity of C3 and C4 complement factors, immunoglobulins, nitric oxide (NO) and total antioxidant capacity (TAC) in opium smokers and non-drug-using control participants. The present study was done on 44 male opium smokers and 44 controls of the same sex and age (20-40 years). The control group was healthy individuals with no lifetime history of drug abuse or dependence. All of the opium abusers were selected from those who had a history of opium use, for at least one year, with a daily opium dosage not less than 2g. Addicts known to abuse alcohol or other drugs were excluded. Serum hs-CRP concentration was measured using ELISA method and serum C3, C4 and immunoglobulins concentration were determined by Single Radial Immunodiffusion (SRID) method. NO production was estimated through Griess reaction and TAC was assessed by Ferric Reducing/Antioxidant Power (FRAP) test. Serum hs-CRP, complement factors (C3 and C4) and FRAP levels were significantly higher in the opium smokers (8.93 ± 1.93; 138.47 ± 13.39; 68.79 ± 7.02 and 972.75 ± 11.55, respectively) relative to the control group (0.72 ± 0.09; 93.36 ± 8.73; 33.08 ± 7.39 and 761.95 ± 18.61, respectively). These results permit us to conclude that opium smokers indeed present with a low to moderate grade inflammation, which is defined by an increase in acute phase proteins.

Cytokine profiles in long-term smokers of opium (Taryak).

OBJECTIVES: There are few studies with conflicting results on the effects of in vivo administration of opioids on immune function. The aim of this study was to evaluate the serum levels of interferon (IFN)-γ, interleukin (IL)-4, IL-10, IL-17, and hs-C-reactive protein (hs-CRP) in opium smokers. METHODS: The study was conducted between 44 male opium addicts and 44 controls aged 20 to 40 years. The control group was healthy individuals with no lifetime history of substance abuse. All the opium abusers were selected from those who had a history of use of opium, as a regular habit, at least for 1 year, with a daily opium dosage of not less than 2 g. Addicts known to abuse alcohol or other drugs were excluded. Serum samples were collected from all participants and tested for the cytokine and hs-CRP levels by ELISA (enzyme-linked immunosorbent assay) method. Statistical analysis was performed using the Student t test. RESULTS: The mean serum levels of IFN-γ, IL-10, and IL-17 in the opium addicts were significantly higher than those observed in the control group. The mean concentration of serum IL-4 in opium addicts did not differ from that in the control group. Systemic IL-10 levels correlated positively and significantly with CRP in opium addicts. CONCLUSIONS: Long-term, daily use of opium is associated with higher Th1 (IFN-γ), Tr1 (IL-10), and Th17 (IL-17) cytokines concentration in serum. Interferon-γ and IL-17 are involved in inducing and mediating proinflammatory responses. Our data suggest that an immunoregulatory response is occurring with the upregulation of IL-10.