Apoptosis cisplatin

Cisplatin is a platinum-based compound (see structure below) that reacts with DNA causing it to crosslink, eventually leading to programmed cell death, also known as apoptosis. Cisplatin was the first in a class of platinum containing anticancer drugs. It has been used to fight several types of cancer and is particularly effective against testicular cancer. 

The pro- and antiapoptotic members of the Bcl2 family affect cellular sensitivity to apoptosis and thus to many chemotherapeutic agents [4]. For example, overexpression of the antiapoptotic genes Bcl2 and Bcl-XL in some cell lines and tumors can confer resistance to apoptosis triggered by ionizing radiation. Conversely, overexpression of proapoptotic Bax in experimental tumors can induce apoptosis directly or render such tumors more sensitive to cisplatin and 5-FU. 

Eastman, A. The Mechanism of Action of Cisplatin From Adducts to Apoptosis. In Cisplatin Chemistry and Biochemistry of a Leading Anticancer Drug Lippert, B., Ed. Wiley-VCH Weinheim, 1999, pp, 111-134. 

Basu A, Cline JS (1995) Oncogenic transformation alters cisplatin induced apoptosis in rat embryo fibroblasts. Int J Cancer 63 597-603 Basu A, Weixel KM (1995) Comparison of protein kinase C activity and isoform expression in cisplatin-sensitive and -resistant ovarian carcinoma cells. Int J Cancer 62 457-460... 

Kondo S, Barnett GH, Kara H, Morimura T, Takeuchi J (1995a) MDM2 protein confers the resistance of a human glioblastoma cell line to cisplatin-induced apoptosis. Oncogene 10 2001-2006... 

Zaffaroni N, Silvestrini R, Orlandi L, Bearzatto A, Gornati D, Villa R. Induction of apoptosis by taxol and cisplatin and effect on cell cycle-related proteins in cisplatin-sensitive and -resistant human ovarian cells. BrJ Cancer 1998 77(9) 1378-1385. 

Investigators found that human breast cancer cell lines with BRCAl mutations showed a twofold to fourfold increase in apoptosis after treatment with ionizing radiation, cisplatin, or doxorubicin, compared with cells free of mutations. They also found that BRCAl tumor cell lines were resistant to other agents, such as paclitaxel (Taxol) and docetaxel (Taxotere), treatments used commonly in ovarian cancer and advanced-stage breast cancers. 

The two guanines are no longer stacked, but the structure is impossible for the trans isomer. The cisplatin adducts appear to prevent proper DNA repair and to induce programmed cell death (apoptosis)/... 

The in vitro antitumor activity of curcumin in HPV-associated cells has been established [Roy et al., 2002]. Curcumin modulates the in vitro expression and function of Pgp in multidrug-resistant human KB-V1 cells [Anand et al., 2008 Chearwae et al., 2004] and sensitizes cisplatin-resistant SiHa cells to cisplatin-induced apoptosis [Venkatraman et al., 2005], indicating its ability to reverse MDR in cervical cancer cells. The effect of curcumin in HPV-associated cells was found to involve the down-regulation of viral oncogenes, NF-kB and AP-1 [Anand et al., 2008 Divya and Pillai, 2006],... 

Venkatraman M, Anto RJ, Nair A, Varghese M, Karunagaran D. 2005. Biological and chemical inhibitors of NF-kappaB sensitize SiHa cells to cisplatin-induced apoptosis. Mol Carcinog 44 51-59. 

Weir NM, Selvendiran K, Kutala VK, Tong L, Vishwanath S, Rajaram M, Tridanda-pani S, Anant S, Kuppusamy P. 2007. Curcumin induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by modulating Akt and p38 MAPK. Cancer Biol Ther 6 178-184. 

Arnold, N.B., Ketterer, K., Kleeff, J, Friess, H., Buchler, M.W, and Korc, M. 2004. Thioredoxin is downstream of Smad7 in a pathway that promotes growth and suppresses cisplatin-induced apoptosis in pancreatic cancer. Cancer Res. 64 3599-3606. 

The piperazinyl derivative showed the greatest in vitro activity, with a mean IC5o value of 1.64 pM over all cell lines, that is, tenfold lower than cisplatin. It was particularly active against the hormone-dependent breast, cervix and ovarian cells, implicating an oestrogenic/anti-oestrogenic effect. This compound also activates caspase-3 in ovarian cells, suggesting that the mechanism of cell death is apoptosis rather than necrosis. 

The benzyl-substituted titanocene 3, which showed a significant higher cytotoxicity when tested in vitro against LLC-PK, was evaluated in a series of biomedical studies as well. Watson et al. tested titanocene 3 in comparison to two aryl-substituted tf .va-titanocenes on prostate cancer cells, as advanced prostate cancer is not curable up to now [37]. Therefore, it was shown that all three titanocenes induced more apoptosis (programmed cell death, in contrast to necrosis) compared with cisplatin in a dose-dependent manner. Titanocene 3 had the most significant effect on the cell cycle and apoptosis. 

The Mechanism of Action of Cisplatin From Adducts to Apoptosis... 

Fig. 4. Possible role of mismatch repair in the cytotoxicity of cisplatin. A) During replicative bypass, a mismatch is incorporated across from the cisplatin-DNA adduct. This compound lesion is bound by the mismatch repair proteins, which cut the DNA on the strand opposite the platinum. Repair synthesis would reproduce the same mismatch, resulting in a futile cycle and possibly the accumulation of DNA strand breaks which would activate apoptosis. B) Alternatively, the mismatch repair complex can recognize the cisplatin-DNA adduct alone and generate a signal that triggers apoptosis.

The formation of cross-links on DNA has the potential to affect directly two essential cellular processes, replication and transcription. Early work demonstrated that cisplatin could inhibit replication under conditions that did not block transcription or translation [2], Adducts formed by trans-DDP can also inhibit DNA polymerases [4], however, and it has become evident that cisplatin lesions are not absolute blocks for replication (see the review by Villiani et al, this book). Furthermore, cisplatin commonly causes an arrest in the G2 phase of the cell cycle [149], suggesting that inhibition of gene expression, and not replication, determines whether the cell will live and divide, or undergo apoptosis. 

The cyclin-dependent kinase inhibitor p21 is another downstream effector of p53 [161-163], There is evidence for p53-independent induction of p21 [162], and under these conditions the protein may be responsible for cisplatin-induced apoptosis [210][211], The p21 protein usually plays a protective role in response to cisplatin [212] [213], however, an effect which correlated with enhanced repair of a damaged reporter plasmid [212-214], These observations are consistent with the hypothesis that DNA-damage induced p53 activates a G, cell cycle arrest through p21, affording the cell time to repair the lesions and precluding the genetic instability produced by replication of damaged DNA. In accord with this model, the addition of p21 to cell free extracts blocked DNA replication but not excision repair... 

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