Apoptosis alkaloids that induce

Table 1. Anticancer alkaloids that induce mitochondria -mediated apoptosis (Intrinsic pathway) in cancer cells...

Apoptosis and necrosis are the two extensively studied modalities of cell deadi that often exhibit similar initiator/effector molecules, signaling pathway s and involving of same organelles [86]. Both types of cell death can co-operate in cellular destruction or can be prevented by autophagy. It has been reported some anti-cancer alkaloids that induce eell death by activation of apoptosis or necrosis, where autophagy participates as a survival and protective pathway (anti-apoptotic or anti-necrotic effect). In these eases, mitoehondria participate at least as a modality of cell death. 

Ganguly et al. [93] demonstrated that (unspecified) tylophora alkaloids could induce apoptosis in a human erythroleukemic cell line (K562) on the basis of nuclear condensation, apoptotic body formation, flipping of membrane phosphatidylserine, activation of caspase 3 and release of mitochondrial cytochrome c. These findings suggest that tylophora alkaloids, in addition to their antiproliferative activity, can also induce apoptosis in certain types of tumor cells. 

Apoptosis can be induced by many substances, among them several natural products, such as alkaloids, that primarily interact with an important molecular target such as DNA or microtubules. Most of the anticancer drugs presently used in cancer therapy lead to apoptosis. The molecular targets associated with cell death and cytotoxicity are discussed in the next section. 

Alkaloids have evolved in plants as powerful defence compounds against herbivores. Although many of them interfere with neuroreceptors and neuronal signal transduction, several others have cytotoxic properties, directed against animal and microbial cells. The present review has tried to summarize some of the molecular targets that are involved in this process. Alkaloids that interfere with microtubules, with DNA (intercalation, topoisomerase inhibition), with protein biosynthesis, and with membrane stability, apparently induce apoptosis, thus leading to cell death. It is very likely however, that many more targets exist that have not been detected, or are not yet correctly understood in this context. 

Ye K, Ke Y, Keshava N, Shanks J, Kapp JA, Tekmal RR, Petros J, Joshi HC. (1998) Opium alkaloid noscapine is an antitumor agent that arrests metaphase and induces apoptosis in dividing cells. Proc Natl Acad Sci USA 95 1601-1606. 

As a whole, the results presented above indicate that low concentrations of Vinca alkaloids, probably similar to therapeutic concentrations, have an antiproliferative activity that is due to inhibition of mitotic spindle function by changing the dynamics of microtubules rather than by depolymerizing them. A growing body of evidence seems to indicate that, specially in cancer cells, where mitosis regulation is already disrupted, the suppression of microtubule dynamics with mitosis arrest induces a signaling cascade leading to cell death by apoptosis (a type of programmed cell death) [172-174]. 

A new alkaloid, stryvomicine A, that contains an unprecedented heptacyclic ring system, was isolated from the seeds of Strychnos nux-vomica (14TL6538). Octahydropyrrolo[2,l-l)][l,3]ox(thi)azepines were found to potendy sensitize previously resistant cancer cell lines to TNF-related apoptosis-inducing ligand (14MCT5). 

In addition to the anticancer indole alkaloids vinblastine and vincristine, discnssed in the next section, many indoles display antitumor activity. Space does not allow complete coverage of these smdies. Indole-3-carbinol (Scheme 12, 75), found in vegetables of genns Brassica (kale, cauliflower, broccoli, turnip, collard, and others), its acid- and/or enzymatic-induced dimer, 3,3 -diindolylmethane (76), and its trimer, 2-(indol-3-yhnethyl)-3,3 -diindolylmethane (77), inhibit cancer cell proliferation and induce apoptosis in several cell lines [88-91]. However, one study reports that... 

Many cells that are no longer of use are eliminated by apoptosis (see Table IV above). Apoptosis can also be induced by a number of toxins and appears to be the major mechanism of cytotoxicity caused by SM. Many polyphenols, terpenoids, saponins, and also alkaloids apparently can induce apoptosis. 

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