Worldwide, cancer has been identified as a significant cause of deaths (Bhanot et al., 2011[26]). Globocan report stated 14.1 million cancer cases in 2012 with 8.2 million deaths worldwide. The most common were cancers of lung, breast and colon. Cancer burden is expected to increase to over 20 million new cases expected in 2025 (Ferlay et al., 2015[43]). The primary objective of the cancer research is to search for novel, less toxic and more potent drug leads which act specifically on cancer cells or search for targeted drug delivery method (Isnard-Bagnis et al., 2005[58]; Phonnok et al., 2010[157]).

About 1000 different plant species have anticancer potential. Plant-based drug discovery process is based on three perspectives:

Determination of bioactivity of the compound including mode of action, its isolation from extract and characterization.

Important plant-based anticancer drugs include Vincristine (Figure 3a(Fig. 3)), Vinblastine (isolated from Madagascan periwinkle, Catharanthus roseus) and Etoposide (Figure 3b(Fig. 3)) isolated from mandrake plant Podophyllum peltatum, which are antimitotic drugs (Bhanot et al., 2011[26]; Noble, 1990[149]). Paclitaxel/ taxol (Figure 3c(Fig. 3)), produced from Pacific yew (Taxus brevifolia) bark is commonly used for treating breast cancers. It promotes tubulin stabilization leading towards apoptosis. Baccatin 3 (Figure 3d(Fig. 3)), a structural analogue of taxol, is isolated from needles of T. brevifolia and converted into taxol efficiently on a commercial scale (Dias et al., 2012[40]; Wilson and Jordan, 1995[179]). Irinotecan (Figure 3e(Fig. 3)) and topotecan (Figure 3f(Fig. 3)) isolated from bark and wood of Camptotheca accuminata have cytotoxic effects on colorectal and ovarian cancers by topoisomerase inhibiting mechanism. Rohitukine (Figure 3g(Fig. 3)), an alkaloid, was obtained from leaves and stems of Dysoxylum binectariferum. Flavopiridol (Figure 3h(Fig. 3)), a flavone synthesized from rohitukine, was the first drug using cyclin-dependent kinase inhibition mechanism. Homoharringtonine (Figure 3i(Fig. 3)), isolated from Cephalotaxus harringtonia, has potency against various leukemias. It works by blocking protein synthesis and cell cycle progression (Bhanot et al., 2011[26]). Euphorbia peplus is a producer of Ingenol 3-angelate (I3A) which has shown potential against various skin cancers and resulted in excellent skin cosmesis in mice. I3A acts as a ligand of protein kinase C (PKC) (Kedei et al., 2004[62]; Ogbourne et al., 2004[151]). Genus Fagonia comprises of various species with health-promoting tendencies. Many species have been reported to accumulate several bioactive compounds such as flavonoids, phenols, alkaloids, tannins, glycolides, saponins, coumarins, sterols and terpenoids. Among these, Fagonia indica has gained interest as a potent anticancer agent. It has been marketed as “virgin's mantle tea” for breast cancer. The extracts of Fagonia indica have also shown antimicrobial, antidiabetic, antioxidant, hepatoprotective, analgesic and anti-inflammatory potential (Khan et al., 2016[66], 2017[65]). Some medicinally important plants and their anticancer compounds are enlisted in Table 2(Tab. 2) (References in Table 2: Amin et al., 2009[18]; Greenwell and Rahman, 2015[51]; Nirmala et al., 2011[148]; Priya et al., 2015[158]; Sain and Sharma, 2013[164]; Sisodiya, 2013[171]; Weaver, 2014[178]).

Marine sponges are immobile in nature. Sponges are said to be the first multicellular organisms and they have diversified very little in about 500 million years (Dias et al., 2012[40]).

The search for marine bioactive compounds began in the 1950s after the isolation of “Spongothymidine” and “Spongouridine” from Crytotheca crypta (Figure 6a and 6b(Fig. 6)). These nucleotides showed great efficacy as antiviral and anticancer drugs (Haefner, 2003[55]). Further exploration of the marine environment became possible after the introduction of Self-Contained Underwater Breathing Apparatus (SCUBA) in the 1970s and remotely operated vehicles (ROVs) in 1990s (Dias et al., 2012[40]).

Another example is “Discodermolide” produced by Discodermia dissolute (Figure 6c(Fig. 6)). This drug has stabilizing action just like taxol and has shown cytotoxic effects against drug-resistant tumors and taxol-resistant tumors in clinical evaluation. Also, combination therapy of discodermolide and taxol showed better tumor reduction in vivo (Huang et al., 2006[56]).

About 30,000 species of algae are inhabitants of marine ecosystems worldwide. Algae have been used as a source of food, medicine and fertilizers by various ethnic groups. Ancient knowledge and ample availability of algal species is the basis of modern algal research. A famous class of compounds isolated from algal species is terpenoids and terpenoid like structures e.g., phenazine derivatives, sterols, brominated oxygen and nitrogen heterocycles, amino acids and amines (Dias et al., 2012[40]; Torres et al., 2014[176]).

Numerous bioactive entities isolated from algae have anti-oxidative, anti-inflammatory and anticancer characteristics. Extracts of red algae, Callophyllis japonica and Gracilaria tenuistipitata have demonstrated anti-oxidative potential. C. japonica enhanced activation of antioxidant enzymes and inhibited hydrogen peroxide (H₂O₂) induced apoptosis. Similarly, extracts of G. tenuistipitata helped in enhanced recovery of human lung carcinoma cells (H1299) from DNA damage (Lee et al., 2013[70]). Ulva lactuca and S. wightii have been reported to produce flavonoids which play role in antioxidant defense system of the body (Meenakshi et al., 2009[77]). Ulva reticulata extracts demonstrated anti-hepatotoxic properties in vivo (Rao et al., 2004[161]).

Several antitumor compounds such as, diterpenes, dictyolides A, B (Figure 7a(Fig. 7)), 4-acetoxydictylolactone and nordictyolide have been isolated from a brown alga, Dictyota dichotoma. Similarly, another brown alga, Dilophus ligatus, is a producer of crenuladial (Figure 7b(Fig. 7)). This compound has shown potent antimicrobial activity against Micrococcus luteus, Aeromonas hydrophyla and Staphylococcus aureus (Dias et al., 2012[40]).

Two species, G. verrucosa and G. textorii have been reported to have anti-inflammatory potential. Another example is Porphyridium spp., from which a retrovirus inhibiting polysaccharide was isolated. Methanolic extract of Neorhodomela aculeate showed suppression of reactive oxygen species (ROS) production, lipid peroxidation and nitric oxide synthase. Beta carotene (Figure 7c(Fig. 7)), obtained from a green algae Dunaliella bardawil, exhibited protective effects against inflamed bowel in mice models. Also, phlorotannins isolated from species of brown algae: Eisenia bicyclis, Ecklonia kurome and Ecklonia cava have shown antioxidant potential (Lee et al., 2013[70]). A blue green alga, Anabaena spp. also showed radical scavenging activity (Pant et al., 2011[154]).

Some species of marine algae possess anticancer potential. Extracts of Gracilaria tenuistipitata were reported to have growth inhibitory effects on Ca9-22 oral cancer cells by causing oxidative stress in cancer cells (Yeh et al., 2012[182]). Another species, Plocamium telfairiae induced apoptosis in HT-29 colon cancer cells. Green algae produce a tertiary sulfonium metabolite called Dimethylsulfoniopropionate (Figure 7d(Fig. 7)), which has significant anticancer potential against Ehrlich ascites carcinoma in vivo. Similarly, heterofucans, isolated from Sargassum filipendula possess anticancer effects against cervical, prostate and liver cancer cells (Lee et al., 2013[70]).

Marine microorganisms are valuable sources of antibacterial, antifungal and antiviral compounds. But the process of marine compounds incorporation in therapeutics is slow because information regarding ethnomedical history is lacking. Today, various pharmaceutical companies have developed programs for isolation and characterization of marine bioactive compounds (Debnath et al., 2007[37]).

Among marine bacteria, Actinomycetes are the largest contributors of novel bioactive secondary metabolites accounting for 45 % of total microbial metabolites (75 % from Streptomyces and 25 % from rare Actinomycetes). A huge variety of antibiotics such as anthracyclines, aminoglycosides, glycopeptides, beta-lactams, macrolides, polyketides, actinomycins and tetracyclines have been isolated from Actinomycetes (Subramani and Aalbersberg, 2012[172]).

Nocardia spp. is a producer of a group of novel maytansinoid antibiotics called “Ansamitocins”. Ansamitocins exhibited significant antitumor and antifungal activities. Vibrio marinus, an isolate of Baltic Sea, it was reported to produce antiviral compounds effective against enteroviruses. A novel antibiotic named “Bushrin” (Figure 8a(Fig. 8), Reference in Figure 8: Ahmed et al., 2008[11]) was extracted from Pseudomonas stutzeri, an isolate of ribbonfish of Baluchistan coast, Pakistan. The compound showed high efficacy against several gram-positive and negative bacteria (Ahmed et al., 2008[11]). Another species, Pseudomonas bromoutilis, was reported to produce a novel pyrrole antibiotic which showed significant inhibition of gram-positive bacteria. Antibiotic MC21-A was isolated from Pseudoalteromonas phenolica which exhibited bactericidal effect (Debnath et al., 2007[37]).

Altemicidin (Figure 8b(Fig. 8)), isolated from Streptomyces sioyaensis had both antitumor and acaricidal activity. It also showed inhibition against Xanthomonas strains (Debnath et al., 2007[37]). Salinosporamide A (Figure 8c(Fig. 8)), obtained from Salinispora tropica was reported to induce apoptosis in multiple myeloma cells (Subramani and Aalbersberg, 2012[172]). Another novel entity, lodopyridone was extracted from genus Saccharomonospora. This alkaloid showed cytotoxicity in human colon adenocarcinoma (HCT-116) cells (Maloney et al., 2009[75]).

Isolation of Arenimycin (Figure 8d(Fig. 8)) antibiotic from Salinispora arenicola was reported by Asolkar et al. (2010[21]). It showed a potent antimicrobial effect against rifampin and methicillin-resistant Enterococcus feacalis, Enterococcus faecium and Staphylococcus aureus. Arenimycin also induced cytotoxicity in human adenocarcinoma cells.

Some bacteria such as Vibrio vulnificus, produce specific proteins called “Bacteriocins” which are bactericidal towards closely related species and are also used for preserving seafood (Shehane and Sizemore, 2002[167]).

Another important discovery was the isolation of bacterium SCRC-2738 from the intestine of Pacific mackerel. This bacterium produced eicosapentaenoic acid (Figure 8e(Fig. 8)) which is used as a preventive and curative agent for thrombosis atherosclerosis (Debnath et al., 2007[37]).

The search for novel microbial metabolites began following the discovery of penicillin (Figure 9a(Fig. 9)) from Penicillium notatum in 1929 by Alexander Fleming. In 1953, another important discovery was the isolation of vancomycin (Figure 9b(Fig. 9)) an antimicrobial agent from Amycolatopsis orientalis. With the advancements in screening methods in the 1970s, several novel antibiotics such as norcardicin, imipenem and aztreonam were discovered (Dias et al., 2012[40]).

Mevinolin (Figure 9c(Fig. 9)), a potent cholesterol-lowering agent was isolated from Aspergillus terreus. Aspercilin was isolated from Aspergillus alliaceus. Later on, benzodiazepines were derived from aspercilin and used for curing anxiety or insomnia (Gurnani et al., 2014[54]). Norsolorinic acid (Figure 9d(Fig. 9)), isolated from Aspergillus spp. was reported to cause apoptosis in breast cancer (MCF-7) and human bladder cancer (T-24) cells (Bladt et al., 2013[28]).

Extracts of Penicillium steckii and Aspergillus sydowii induced cytotoxicity in human cervical carcinoma cell line (HeLa) (Fajarningsih et al., 2013[42]). Whereas, extract of Alternaria alternata showed cytotoxic activity against Staphylococcus aureus, Escherichia coli and HeLa cells (Fernandes et al., 2009[44]). Similarly, Wu et al. (2014[180]) reported that ethanolic extracts of Fomitopsis pinicola induce cytotoxicity in various cancer cell lines including human hepatoma, colorectal, lung and breast cancer cells along with synergistic effects with cisplatin in vivo.

Many fungal species called endophytic fungi are inhabitants of intracellular spaces of plants without imposing harm. Various endophytic fungi have been investigated for bioactive compounds. One such example is Cryptosporiopsis quercina, isolated from Tripterigeum wilfordii (medicinal plant). It has shown potent antifungal activity against Candida albicans and Trycophyton mentagrophyte. Another endophytic fungus, Aspergillus parasiticus, isolated from Sequoia sempervirens was reported to be a producer of sequoiatones A and B (Figure 9e and 9f(Fig. 9)) which showed moderate anticancer potential with the highest activity against breast cancer cell lines. Torreyanic acid (Figure 9g(Fig. 9)), isolated from endophytic fungi of Torreya taxifolia tree exhibited apoptotic activity in protein kinase C sensitive cancer cells (Dias et al., 2012[40]; Gurnani et al., 2014[54]).

Endophytic fungi, Taxomyces andreanae and Nodulisporium sylyiforme have been reported to produce taxol (an anticancer drug previously isolated from the pacific yew tree). Along with anticancer potential, this drug also exhibited antifungal activity against Pythium, Phytophthora and Aphanomyces spp. (Gupta et al., 2014[53]).

A novel polykedite, 5-hydroxyramulosin (Figure 9h(Fig. 9)) isolated from an endophytic fungus of Cinnamomum mollissimum showed both antifungal activities against Aspergillus niger and anticancer activity against murine leukemia cells (Santiago et al., 2012[166]). Helvolic acid (Figure 9i(Fig. 9)) and ergosterol peroxide (Figure 9j(Fig. 9)) obtained from endophyte Pichia guilliermondii inhabitant of Paris polyphylla var. yunnanensis plant have shown significantly strong antimicrobial activities against various bacterial pathogens (Zhao et al., 2010[186]).

Natural habitats including soil, plant-associated environments, acidic water bodies, geothermal vents, high pH lakes, metal mining sites, extremely cold deserts, hot springs, marine soil sediments, radioactive waste disposal areas and many others are dwelling with a huge variety of microbes which are producers of structurally diverse compounds (Mahajan and Balachandran, 2014[73]). The extent of biodiversity among bacterial strains is much higher than that of plants and animals. For example, two bacterial strains, Escherichia coli and Bacillus subtilis are genetically more variable from each other than humans are from corns (Clardy, 2007[34]).

The search for bacterial metabolites in the field of therapeutics began after the discovery of an antibiotic, “Actinomycin” (Figure 10a(Fig. 10)) from gram-positive Actinomycetes in 1940. After that, many prominent anticancer drugs were isolated such as anthracyclines (daunorubicin, doxorubicin, epirubicin, pirarubicin and valrubicin), bleomycin, mitosanes (mitomycin C), anthracenones (mithramycin, streptozotocin and pentostatin), enediynes (calicheamicin), taxol and epothilones. Majority of them were isolated from Streptomyces spp. (Gupta et al., 2014[53]).

Nisin (Figure 10b(Fig. 10)), a bacteriocin has been used as bio-preservative (Gupta et al., 2014[53]). Rapamycin (Figure 10c(Fig. 10)), an antifungal agent was isolated from soil inhabiting Actinomycetes. It is also used for inhibiting organ rejection in transplant patients (Clardy, 2007[34]).

Amrubicin hydrochloride (Figure 10d(Fig. 10)), an anticancer compound was isolated from Streptomyces peucetius in 2002 (Dias et al., 2012[40]; Gurnani et al., 2014[54]). A new class of antibiotics called Pumalicidins A, B, C, D, E, F and G were obtained from the culture broth of Bacillus pumilus. Pumalicidin B resulted in 68 % reduction of Shay ulcers in vivo (Gupta et al., 2014[53]).

Homologues of Bacillomycin D, isolated from Bacillus subtillis (B38) were reported to have anti-oxidative and DNA protective activities (Singla et al., 2014[170]). Additionally, Surfactin, produced by Bacillus subtilis CYS191, was reported to induce apoptosis in human breast cancer cells (MCF-7) by causing oxidative stress (Cao et al., 2010[32]). Streptomyces hygroscopicus was identified as a producer of antifungal prenylated indole, galbonolides A and B, elaiophylin and its derivatives and herbimycins. Pterocidin, produced by endophytic Streptomyces hygroscopicus showed cytotoxic effects in human lung, ovarian, glioblastoma and melanoma cells (Igarashi et al., 2006[57]). Novel Methoxyneihumicin and Diketopiperazine isolated from Nocardiopsis alba exhibited anticancer activity (Singla et al., 2014[170]).

Various strains of Pseudomonas aeruginosa have the ability to produce a copper-containing redox protein called azurin. Presence of copper gives azurin a number of properties which include blue colour and redox potential. Various domains of the protein are involved in anticancer, anti-parasitic and anti-HIV activities (Osman et al., 2013[152]). Punj et al. (2004[159]) reported that cytotoxic activity of azurin was largely dependent on the presence of p53 gene. Similarly, an analogue of signal peptide 27, produced by Streptococcus pneumoniae has shown cytotoxicity against leukemia, gastric and breast cancer by cellular permeabilization and induction of caspase-independent apoptosis. Another anticancer peptide Entap (Enterococcal anti-proliferative peptide) isolated from Enterococcus spp. cause induction of autophagous apoptosis and inhibits proliferation in several cancers (Karpinski and Szkaradkiewicz, 2013[61]).

Recently, bacterial toxins are gaining interest in targeted cancer therapy (Table 3(Tab. 3); References in Table 3: Foss, 2000[46]; Karpinski and Szkaradkiewicz, 2013[61]; Nair at al., 2014[80]; Pahle et al., 2017[153]; Patyar et al., 2010[155]; Yang et al., 2013[181]; Zahaf and Schmidt, 2017[183]). They are produced naturally as virulence factors by various strains of pathogenic bacteria. High stability and immunogenicity make them well-suited candidates for cancer therapy. Bacterial toxins are now being used as immunotoxins which contain a toxin moiety attached to a target-specific antibody (Becker and Benhar, 2012[22]).