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S. D. Shnyder and C. W. Wright
9 Cytotoxic and Antineoplastic Activity
9.1 Cytotoxic Mechanisms of Action
Since a previous review in 2008 [1], further information of the mechanism of action
of 1 and its analogs has been elucidated, and more active analogs have been synthesized and identified. The range of cancer types where activity has been seen has
expanded, although not all studies reviewed have evaluated or demonstrated differential activity between cancerous and normal cells. Therefore, a caveat has to be
added to these studies as to whether the activity seen is broadly cytotoxic, or cancerspecific. Interestingly, recent studies have been published where 1 and its analogs
have been progressed to evaluation in animal models, giving stronger support to the
possible use of the cryptolepines in cancer therapy [56–58].
The mechanism of activity of 1 itself has been further investigated. In an extensive study [59], 1 was evaluated against a panel of eight cell lines, and drugresistant sublines (CCRF-CEM T-cell leukemia, and its teniposide-resistant subline
CEM/VM-1; RPMI 8226-S multiple myeloma, and its doxorubin- and melphalanresistant sublines 8226/Dox and 8226/LR5; U-937-GTB histiocytic lymphoma and
its vincristine-resistant subline U-937/Vcr; NCI-H69 small cell lung cancer and its
doxorubicin-resistant subline H69/AR; ACHN renal adenocarcinoma; Hela cervical
adenocarcinoma, as well as hTERT-RPE immortalized normal retinal epithelial
cells), in addition to cell isolates from 32 hematological and 34 solid tumor patient
samples. The mean IC 50 value for the cell line panel was 0.9±0.2 μM, and was similar
to the hematological malignancies (1.0±0.2 μM). For solid tumors, the mean IC 50
was higher (2.8±1.2 μM), but it was found that individual samples from breast, colon,
and non-small cell lung cancer patients were highly sensitive. An interesting finding
was that sensitive cell lines expressing established anticancer drug resistance mechanisms are sensitive to 1, which further strengthens its potential for development.
When gene expression analysis was carried out, it was seen that in addition to the
known mechanisms associated with 1 of topoisomerase II inhibition and DNA intercalation, correlations were also observed with genes associated with microtubule
inhibition, extracellular matrix metalloproteinase inhibition, perturbation of intramembrane transport, NF-κB perturbation, proteasome inhibition, respiratory chain
inhibition, and induction of chemical hypoxia and hypoxia-selective cytotoxicity
[59]. As mentioned elsewhere in this contribution, 1 is involved in NF-κB inhibition
[27], and a review by Ansah and Mensah from 2013 suggested that one of the mechanisms of its antineoplastic activity may be through its anti-inflammatory activity
[60]. In another study, 1 isolated from Sida acuta acted as a sensitizer in the AGS
human gastric cancer cell line to tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) through activation of caspase 3/7 [61]. DNA damage induced by
1 was seen to be linked to a loss of mitochondrial membrane potential (MMP)
and a subsequent release of cytochrome c as a cause of cell death in studies using
melanoma [56] and non-melanoma skin cancer cell lines [62]. In the latter study, in
addition to disruption of MMP, DNA damage induced by 1 also led to increases in
S. D. Shnyder and C. W. Wright
9 Cytotoxic and Antineoplastic Activity
9.1 Cytotoxic Mechanisms of Action
Since a previous review in 2008 [1], further information of the mechanism of action
of 1 and its analogs has been elucidated, and more active analogs have been synthesized and identified. The range of cancer types where activity has been seen has
expanded, although not all studies reviewed have evaluated or demonstrated differential activity between cancerous and normal cells. Therefore, a caveat has to be
added to these studies as to whether the activity seen is broadly cytotoxic, or cancerspecific. Interestingly, recent studies have been published where 1 and its analogs
have been progressed to evaluation in animal models, giving stronger support to the
possible use of the cryptolepines in cancer therapy [56–58].
The mechanism of activity of 1 itself has been further investigated. In an extensive study [59], 1 was evaluated against a panel of eight cell lines, and drugresistant sublines (CCRF-CEM T-cell leukemia, and its teniposide-resistant subline
CEM/VM-1; RPMI 8226-S multiple myeloma, and its doxorubin- and melphalanresistant sublines 8226/Dox and 8226/LR5; U-937-GTB histiocytic lymphoma and
its vincristine-resistant subline U-937/Vcr; NCI-H69 small cell lung cancer and its
doxorubicin-resistant subline H69/AR; ACHN renal adenocarcinoma; Hela cervical
adenocarcinoma, as well as hTERT-RPE immortalized normal retinal epithelial
cells), in addition to cell isolates from 32 hematological and 34 solid tumor patient
samples. The mean IC 50 value for the cell line panel was 0.9±0.2 μM, and was similar
to the hematological malignancies (1.0±0.2 μM). For solid tumors, the mean IC 50
was higher (2.8±1.2 μM), but it was found that individual samples from breast, colon,
and non-small cell lung cancer patients were highly sensitive. An interesting finding
was that sensitive cell lines expressing established anticancer drug resistance mechanisms are sensitive to 1, which further strengthens its potential for development.
When gene expression analysis was carried out, it was seen that in addition to the
known mechanisms associated with 1 of topoisomerase II inhibition and DNA intercalation, correlations were also observed with genes associated with microtubule
inhibition, extracellular matrix metalloproteinase inhibition, perturbation of intramembrane transport, NF-κB perturbation, proteasome inhibition, respiratory chain
inhibition, and induction of chemical hypoxia and hypoxia-selective cytotoxicity
[59]. As mentioned elsewhere in this contribution, 1 is involved in NF-κB inhibition
[27], and a review by Ansah and Mensah from 2013 suggested that one of the mechanisms of its antineoplastic activity may be through its anti-inflammatory activity
[60]. In another study, 1 isolated from Sida acuta acted as a sensitizer in the AGS
human gastric cancer cell line to tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL) through activation of caspase 3/7 [61]. DNA damage induced by
1 was seen to be linked to a loss of mitochondrial membrane potential (MMP)
and a subsequent release of cytochrome c as a cause of cell death in studies using
melanoma [56] and non-melanoma skin cancer cell lines [62]. In the latter study, in
addition to disruption of MMP, DNA damage induced by 1 also led to increases in