Elevated rates of reactive oxygen species (ROS) have been detected in almost all cancers, where they promote many aspects of tumour development and progression. However, tumour cells also express increased levels of antioxidant proteins to detoxify from ROS, suggesting that a delicate balance of intracellular ROS levels is required for cancer cell function. Further, the radical generated, the location of its generation, as well as the local concentration is important for the cellular functions of ROS in cancer. A challenge for novel therapeutic strategies will be the fine tuning of intracellular ROS signalling to effectively deprive cells from ROS-induced tumour promoting events, towards tipping the balance to ROS-induced apoptotic signalling. Alternatively, therapeutic antioxidants may prevent early events in tumour development, where ROS are important. However, to effectively target cancer cells specific ROS-sensing signalling pathways that mediate the diverse stress-regulated cellular functions need to be identified. This review discusses the generation of ROS within tumour cells, their detoxification, their cellular effects, as well as the major signalling cascades they utilize, but also provides an outlook on their modulation in therapeutics.

/pdf/reactive-oxygen-species-in-cancer-2cc2eau8py.pdf

Reactive oxygen species in cancer

The indole ring system is present in many natural products, pharmaceuticals, agrochemicals, and other compounds of importance.1–8 The indole unit forms the basis for general BIM and TIM structures (Figure 1). The main purpose of this review is to provide a comprehensive summary of the various synthetic strategies to synthesize BIMs and TIMs. A number of BIM and TIM applications will be briefly pointed out, although this is not the main aim of this review. Many of the most important BIMs and TIMs were widely isolated from various terrestrial and marine natural sources. These natural products have novel structures and exhibit a range of important biological activities.9–19 Cancer chemotherapy with bis(3-indolyl)methane was recently reviewed and numerous activities are reported.20 3,3′-Diindolylmethane and derivatives also are used as dietary supplements for humans.21–24 BIMs inhibit bladder cancer growth,25 inhibit renal cell carcinoma growth,26 have growth inhibitory activity on lung cancer cells,27 are active against colon cancer,28,29 inhibit mammary tumor growth,30,31 induce apoptosis in prostate cancer,32–34 inhibit the proliferation process in breast tumor cells,35–50 have growth inhibitory activity on prostate cancer cell lines,51,52 have antitumorigenic activity,53 serve as topoisomerase IIR catalytic inhibitors,54 serve as inhibitors of the platelet-derived growth factor receptor kinase,55 exhibit antimicrobial and antifungal activities,56,57 exhibit antibiotic activity58 and antibacterial activity,59 have inhibitory effects on phenobarbital-induced hepatic CYP mRNA expression,60 serve as cytodifferentiating agents,61 are antiangiogenic and cytotoxic agents,62 have antimetastatic activity,63 have radical scavenging activity,64 growth promoting activity,65 and analgesic and anti-inflammatory activities,66 and are also utilized as tranquilizers67 and glass-forming high-tripletenergy materials.68 The oxidized form of BIMs and TIMs are utilized as dyes,69–74 as well as colorimetric sensors.75–78 A patent79,80 disclosed the synthetic method of chromogenic 3,3′-bisindolyl-4-azaphthalides 1 and their uses as color formers in pressureand heat-sensitive recording materials (Figure 2).81 A recent patent describes the synthesis of BIMs forming complexes 2 with radioactive metal ions (Gd3+), which are useful contrast agents for radio-imaging and visualization of various tissues and organs (Figure 2).82 Recently Maciejewska et al.83 used DNA-based electrochemical biosensors to demonstrate that bis(5-methoxyindol3-yl) methane, 3,84 considerably reduces the growth of cancer cell lines such as HOP-92 (lung), A498 (renal), and MDAMB-231/1TCC (breast) (Figure 3). Their results also indicate that BIMs could potentially be applied as chemotherapeutic agents against tumors.83,85 Recently Lee and co-workers have found that 1,1,3-tri(3indolyl)cyclohexane, 4, inhibits cancer cell growth in lung cancer cells of xenograft models (Figure 4).86 Ghaedi et al.87,88 have used BIMs coated on an aluminasodium dodecyl sulfate (SDS) surface for preconcentration and determination of Cu(II), Zn(II), Pb(II), and Fe(III) ions by flame atomic absorption spectrometry. Also BIMs and TIMs have been used as ligands for the synthesis of more complex molecules, and different properties of these complexed molecules have been investigated.89–94 † This paper is dedicated to Prof. Dr. Junes Ipaktschi on occasion of his 70th birthday. * To whom correspondence should be addressed. Fax: +98 21 88041344. E-mail: mshiri@alzahra.ac.ir. ‡ Alzahra University. § Bu-Ali Sina University. ⊥ University of KwaZulu-Natal. Figure 1. The structure of BIMs and TIMs. Chem. Rev. 2010, 110, 2250–2293 2250

Bis- and Trisindolylmethanes (BIMs and TIMs)†

Indoles are natural products well known for their anticancer activity, which is related to their ability to induce cell death for many cancer cell lines. This review addresses indoles as natural products, mechanism of indoles, facilitated induction and recent studies with indoles and related compounds that were investigated via anticancer screening and that led to drug approval.

Indoles as anticancer agents

The activation of ethyl bromofluoroacetate employing a visible light mediated, Eosin Y catalyzed photoredox transformation is reported. Using indoles and anilines as nucleophiles, the reaction leads to the formation of two Csp2–Csp3 bonds resulting in an efficient synthesis of bisindolyl and bisanilinoyl acetate derivatives. Application of this method to the direct synthesis of unsymmetrical diarylacetates featuring indoles and N-substituted anilines was also demonstrated.

Visible Light Mediated Organocatalytic Activation of Ethyl Bromofluoroacetate: Coupling with Indoles and Anilines

Biopolymeric alginic acid: an efficient recyclable green catalyst for the Friedel–Crafts reaction of indoles with isoquinoline-1,3,4-triones in water

BACKGROUND. The clinical responses to chemotherapy in lung cancer patients are unsatisfactory. Thus, the development of more effective anticancer drugs for lung cancer is urgently needed. METHODS. A 2-step novel synthetic compound, referred to as 1,1,3-tri(3-indolyl)cyclohexane (3-indole), was generated in high purity and yield. 3-Indole was tested for its biologic activity in A549, H1299, H1435, CL1-1, and H1437 lung cancer cells. Animal studies were also performed. RESULTS. The data indicate that 3-indole induced apoptosis in various lung cancer cells. Increased cytochrome-c release from mitochondria to cytosol, decreased expression of antiapoptotic Bcl-2, and increased expression of proapoptotic Bax were observed. In addition, 3-indole stimulated caspases-3, -9, and to a lesser extent caspase-8 activities in cancer cells, suggesting that the intrinsic mitochondria pathway was the potential mechanism involved in 3-indole-induced apoptosis. 3Indole-induced a concentration-dependent mitochondrial membrane potential dissipation and an increase in reactive oxygen species (ROS) production. Activation of c-Jun N-terminal kinase (JNK) and triggering of DNA damage were also apparent. Note that 3-indole-induced JNK activation and DNA damage can be partially suppressed by an ROS inhibitor. Apoptosis induced by 3-indole could be abrogated by ROS or JNK inhibitors, suggesting the importance of ROS and JNK stress-related pathways in 3-indole-induced apoptosis. Moreover, 3-indole showed in vivo antitumor activities against human xenografts in murine models. CONCLUSIONS. On the basis of its potent anticancer activity in cell and animal models, the data suggest that this 2-step synthetic 3-indole compound of high purity and yield is a potential candidate to be tested as a lead pharmaceutical compound for cancer treatment. Cancer 2008;113:815–25. � 2008 American Cancer Society.

http://www.biol.ntnu.edu.tw/files/writing_journal/8/104_8ed49295.pdf

Novel 2-step synthetic indole compound 1,1,3-tri(3-indolyl)cyclohexane inhibits cancer cell growth in lung cancer cells and xenograft models.

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Novel 2-step synthetic indole compound 1,1,3-tri(3-indolyl)cyclohexane inhibits cancer cell growth in lung cancer cells and xenograft models.