Marine Algal Bioactivities 127
Hypoxia-inducible factor 1 (HIF-1) is an important molecule as it regulates the transcription of
many of the genes involved in key aspects of cancer biology, including immortalization, maintenance of
stem cell pools, cellular dedifferentiation, genetic instability, vascularization, metabolic reprogramming,
autocrine growth factor signalling, invasion/metastasis, and treatment failure. In general, HIF-1 promotes
tumour cell adaptation and survival under hypoxic conditions (Mohammed et al. 2004). Thus, specific
HIF-1 inhibitors are validated as an important class of potential tumour-selective therapeutic agents. In
further support of this conclusion, immunohistochemical detection of HIF-1 overexpression in biopsy
sections is a prognostic factor in many cancers. Gaining insight into the cell and molecular biology of
cancer cells and how they survive and spread has led to additional lines of research involving bioactive
compounds from algae. For example, using a T47D human breast tumour cell-based luciferase reporter
assay to monitor HIF-1 activity, extracts from the red alga Laurencia intricata (Rhodomelaceae) were
evaluated for HIF-1 inhibitory activity. The bioassay-guided fractionation of the lipid extract of a
Jamaican collection of the red alga Laurencia intricata yielded the first marine natural product inhibiting
HIF-1 activation (Mohammed et al. 2004). The active compound was a structurally novel bicyclic
diterpene called laurenditerpenol that inhibited hypoxia (1% O 2 )-induced HIF-1 activation in T47D
cells (IC 50 = 0.4 μM). Laurenditerpenol was shown to inhibit HIF-1 activation by blocking hypoxiainduced HIF-1α protein accumulation. Respiration studies established that laurenditerpenol suppresses
mitochondrial oxygen consumption at the electron transport complex I (IC 50 = 0.8 μM). Further studies
with laurenditerpenol were hindered by a lack of compound supply. However, total synthesis has resolved
the absolute configuration of laurenditerpenol (Chittiboyina et al. 2007) and together with other synthetic
efforts (e.g., Jung and Im 2008) may provide sufficient compound to allow further evaluation as a
potential chemotherapeutic agent.
The preclinical pharmacology of dehydrothyrsiferol (DT), a polyether triterpenoid isolated from a
Canary island collection of the red alga Laurencia viridis, was evaluated by the biochemical nature of the
cytotoxic effect of DT on the human oestrogen receptor+ (ER+) and oestrogen receptor¯ (ER¯) breast
cancer cell lines (Pec et al. 2003). Although they were able to exclude the possibility that DT functions as a
mitotic inhibitor, they noted that induction of apoptosis was induced more efficiently and with distinct cell
cycle-related patterns in the more aggressive ER¯ cells’ while being less complete in ER+ breast cancer
cell lines. Moreover, other polyether triterpenoids such as iubol, 22-hydroxy-15(28)-dehydrovenustatriol
and secodehydrothyrsiferol isolated from the latter alga showed effectiveness against Jurkat leukemic
cells (IC 50 = 2.0–3.5 μM). The capacity of the above compounds to inhibit cell proliferation was likely
due to their ability to induce apoptosis, as assessed by the appearance of a sub-G1/G0 subpopulation in
cell cycle analysis, indicative of DNA breakdown (Pacheco et al. 2011). Two cyclized meroditerpenoids,
atomarianones A and B, were isolated from the organic extract of the brown alga Taonia atomaria collected
at Serifos island in the Central Aegean Sea. The cytotoxicity of atomarianones A and B was assayed
against NSCLC-N6 and A549 lung cancer cell lines. Both metabolites showed significant cytotoxicity
in the two cell lines with IC 50 values < 7.35 µM (Abatis et al. 2005). Halogenated monoterpenes isolated
from the red alga Plocamium cartilagineum were evaluated for their cytotoxic effects on murine colon
adenocarcinoma CT26, human colon adenocarcinoma SW480, human cervical adenocarcinoma HeLa,
and human malignant melanoma SkMel28 cells as well as on the mammalian non-tumoural cell line CHO
(Chinese hamster ovary cells). Four of the nine isolated monoterpenes exhibited selective cytotoxicity
against colon and cervical adenocarcinoma cells. Interestingly, the effect of one of the compounds
was specific and irreversible to human colon adenocarcinoma SW480 cells, which overexpress the
transmembrane P-glycoprotein, a drug efllux transporter often related to chemoresistance. None of the
anti-tumoural doses of these compounds was cytotoxic against CHO cells (de Inés et al. 2004).
Certain polysaccharides are known to inhibit proliferation of different cancer cell lines. The
extracellular acidic polysaccharide GA3P, a D-galactan sulphate associated with L-(+)-lactic acid
produced by the marine microalga Gymnodinium sp., has been shown to be a potent inhibitor of the
DNA topoisomerases I and II (Umemura et al. 2003). Furthermore, GA3P exhibited moderate in vitro
cytotoxicity against 38 human tumours (IC 50 values ranged from 0.67 to 11 µg/mL; Umemura et al.
2003). Fucose-containing sulphated polysaccharides extracted from Sargassum henslowianum and Fucus
vesiculosus decreased the proliferation of melanoma cells in a dose-response manner via induction of
Hypoxia-inducible factor 1 (HIF-1) is an important molecule as it regulates the transcription of
many of the genes involved in key aspects of cancer biology, including immortalization, maintenance of
stem cell pools, cellular dedifferentiation, genetic instability, vascularization, metabolic reprogramming,
autocrine growth factor signalling, invasion/metastasis, and treatment failure. In general, HIF-1 promotes
tumour cell adaptation and survival under hypoxic conditions (Mohammed et al. 2004). Thus, specific
HIF-1 inhibitors are validated as an important class of potential tumour-selective therapeutic agents. In
further support of this conclusion, immunohistochemical detection of HIF-1 overexpression in biopsy
sections is a prognostic factor in many cancers. Gaining insight into the cell and molecular biology of
cancer cells and how they survive and spread has led to additional lines of research involving bioactive
compounds from algae. For example, using a T47D human breast tumour cell-based luciferase reporter
assay to monitor HIF-1 activity, extracts from the red alga Laurencia intricata (Rhodomelaceae) were
evaluated for HIF-1 inhibitory activity. The bioassay-guided fractionation of the lipid extract of a
Jamaican collection of the red alga Laurencia intricata yielded the first marine natural product inhibiting
HIF-1 activation (Mohammed et al. 2004). The active compound was a structurally novel bicyclic
diterpene called laurenditerpenol that inhibited hypoxia (1% O 2 )-induced HIF-1 activation in T47D
cells (IC 50 = 0.4 μM). Laurenditerpenol was shown to inhibit HIF-1 activation by blocking hypoxiainduced HIF-1α protein accumulation. Respiration studies established that laurenditerpenol suppresses
mitochondrial oxygen consumption at the electron transport complex I (IC 50 = 0.8 μM). Further studies
with laurenditerpenol were hindered by a lack of compound supply. However, total synthesis has resolved
the absolute configuration of laurenditerpenol (Chittiboyina et al. 2007) and together with other synthetic
efforts (e.g., Jung and Im 2008) may provide sufficient compound to allow further evaluation as a
potential chemotherapeutic agent.
The preclinical pharmacology of dehydrothyrsiferol (DT), a polyether triterpenoid isolated from a
Canary island collection of the red alga Laurencia viridis, was evaluated by the biochemical nature of the
cytotoxic effect of DT on the human oestrogen receptor+ (ER+) and oestrogen receptor¯ (ER¯) breast
cancer cell lines (Pec et al. 2003). Although they were able to exclude the possibility that DT functions as a
mitotic inhibitor, they noted that induction of apoptosis was induced more efficiently and with distinct cell
cycle-related patterns in the more aggressive ER¯ cells’ while being less complete in ER+ breast cancer
cell lines. Moreover, other polyether triterpenoids such as iubol, 22-hydroxy-15(28)-dehydrovenustatriol
and secodehydrothyrsiferol isolated from the latter alga showed effectiveness against Jurkat leukemic
cells (IC 50 = 2.0–3.5 μM). The capacity of the above compounds to inhibit cell proliferation was likely
due to their ability to induce apoptosis, as assessed by the appearance of a sub-G1/G0 subpopulation in
cell cycle analysis, indicative of DNA breakdown (Pacheco et al. 2011). Two cyclized meroditerpenoids,
atomarianones A and B, were isolated from the organic extract of the brown alga Taonia atomaria collected
at Serifos island in the Central Aegean Sea. The cytotoxicity of atomarianones A and B was assayed
against NSCLC-N6 and A549 lung cancer cell lines. Both metabolites showed significant cytotoxicity
in the two cell lines with IC 50 values < 7.35 µM (Abatis et al. 2005). Halogenated monoterpenes isolated
from the red alga Plocamium cartilagineum were evaluated for their cytotoxic effects on murine colon
adenocarcinoma CT26, human colon adenocarcinoma SW480, human cervical adenocarcinoma HeLa,
and human malignant melanoma SkMel28 cells as well as on the mammalian non-tumoural cell line CHO
(Chinese hamster ovary cells). Four of the nine isolated monoterpenes exhibited selective cytotoxicity
against colon and cervical adenocarcinoma cells. Interestingly, the effect of one of the compounds
was specific and irreversible to human colon adenocarcinoma SW480 cells, which overexpress the
transmembrane P-glycoprotein, a drug efllux transporter often related to chemoresistance. None of the
anti-tumoural doses of these compounds was cytotoxic against CHO cells (de Inés et al. 2004).
Certain polysaccharides are known to inhibit proliferation of different cancer cell lines. The
extracellular acidic polysaccharide GA3P, a D-galactan sulphate associated with L-(+)-lactic acid
produced by the marine microalga Gymnodinium sp., has been shown to be a potent inhibitor of the
DNA topoisomerases I and II (Umemura et al. 2003). Furthermore, GA3P exhibited moderate in vitro
cytotoxicity against 38 human tumours (IC 50 values ranged from 0.67 to 11 µg/mL; Umemura et al.
2003). Fucose-containing sulphated polysaccharides extracted from Sargassum henslowianum and Fucus
vesiculosus decreased the proliferation of melanoma cells in a dose-response manner via induction of