Cisplatin resistant cancer cell

Uchiumi T, Hinoshita E, Haga S, Nakamura T, Tanaka T, Toh S et al. Isolation of a novel human canalicular multispecific organic anion transporter, cMOAT2/MRP3, and its expression in cisplatin-resistant cancer cells with decreased ATP-dependent drug transport. Biochem Biophys Res Commun 1998 252(1)703-110. 

Important was the finding [75] that these ](ri -arene)Ru(N,N)Cl] complexes are equally potent towards wild-type and cisplatin-resistant cancer cells in culture. This suggested that the mechanism of action was different from cisplatin. 

SH-SY5Y neuroblastoma, cisplatin-sensitive A2780 and cispla-tin-resistant A2780cis human ovarian cancer cells was observed, but upon irradiation 7 strongly reduced the viability of the cancer cells (Fig. 8). In the A2780 cell line, the complex was 80x more toxic than cisplatin under identical conditions, and ca. 15 x more effective against the cisplatin-resistant A2780cis cell line (33). The trans diazido-Pt(IV) complex therefore has remarkable cytotoxic properties. 

Andrews PA, Howell SB. Cellular pharmacology of cisplatin perspective on mechanisms of acquired resistance. Cancer Cells 1990 2 35 43. 

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],... 

Heptaplatin (cis-malonate[(4i ,5i )-4,5-bis(aminomethyl)-2-isopropyl-l,3-dioxolane]platinum(II), SKT2053R, Sunpla) has high antitumor activity against various cancer cell lines, including cisplatin-resistant tumor cells. PreUminary results suggested that it is less nephrotoxic than cisplatin. However, a comparative trial showed that intravenous heptaplatin 400 mg/m was more nephrotoxic than intravenous cisplatin 60 mg/m in terms of uremia and proteinuria, which occurred despite the use of hyperosmolar mannitol and appropriate concomitant hydration (fluid intake at least 3500 ml/day) (34,35). 

The cytotoxicity of cisplatin originates from the hydrolysis facility of the chlorine, its binding to DNA, and the formation of covalent cross-links. One disadvantage of cisplatin is its limited solubility in aqueous solutions and its intravenous administration. Platinum complexes with distinctively different DNA binding modes from those of cisplatin may provide higher antitumor activity against cis-platin-resistant cancer cells. 

Dyshlovoy SA, Venz S, Shubina LK, Fedorov SN, Walther R, Jacobsen C, et al. Activity of aaptamine and two derivatives, demethyloxyaaptamine and isoaapta-mine, in cisplatin-resistant germ cell cancer. J Proteomics 2014 96 223-9. 

Protein kinase C influenced cellular sensitivity to cisplatin. Activators of protein kinase C, such as phorbol 12,13-dibutyrate, enhanced the sensitivity of human small cell lung cancer H69 cells to cisplatin by 2-fold but had no effect on the sensitivity of cisplatin-resistant H69 cells to cisplatin (Busu et al. 1996). The maximum sensitisation was achieved with 10 nM phorbol 12,13-dibutyrate and blocked by down-regulation of protein kinase C with higher concentrations of phorbol 12,13-dibutyrate (1 jiM) or bryostatin 1 (0.1 p,M). H69 cells expressed conventional protein kinase Ca and -P, novel protein kinase C6, atypical protein kinase and -i, and novel/atypical protein kinase Cp,. A decrease in conventional protein kinase Ca and -P and an increase in novel protein kinase C6 were associated with the cisplatin-resistant phenotype. 

Andrews PA, Howell SB (1990) Cellular pharmacology of cisplatin perspectives on mechanisms of acquired resistance. Cancer Cells 2 35-43 Andrews PA, Murphy MP, Howell SB (1987) Metallothionein-mediated cisplatin resistance in human ovarian carcinoma cells. Cancer Chemother Pharmacol 19 149-154... 

Dimeric complexes like [Cl(NH3)Pt H2N(CH2)4NH2 Pt(NH3)Cl]Cl2 are also being investigated as they bind to DNA in a different way to that involved in cisplatin binding and are active in cisplatin-resistant human tumour cells. They are more potent than cisplatin in lung cancer models in vivo and are likely to go on clinical trials in the near future [204],... 

Kawakami, M., Kagotani, K., Okumura, K., Akiyama, S., Kuwano, M., A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation, Cancer Res. 1996, 56, 4124-4129. 

In phase I clinical trials 47 patients, all of whom had previously failed standard treatments for solid tumors, received the drug in the UK, Italy, and Switzerland on three different schedules.123,124 Dose-limiting toxicities have been defined as bone marrow depression and diarrhea. The latter is treatable with loperamide. Signs of biological activity were seen. Notably one patient with metastatic pancreatic cancer showed a partial response (for 4 months) and two further patients, one with metastatic melanoma and one with bronchoalveolar carcinoma, also showed partial responses. In a phase I trial in combination with 5-FU, a partial response in breast cancer was observed.125 Furthermore, a reduction in tumor marker levels was observed in two patients, one with ovarian cancer, and one with colon cancer. Phase II studies have shown partial responses in cisplatin-resistant ovarian and nonsmall-cell lung cancer.126,127 The indications are that the profile of clinical activity is different and complementary to the mononuclear platinum agents. 

Fig. 7. Effect of light on the IC50 values for the inhibition of cell growth of various cancer cell lines by platinum(IV) diazido complexes, (a) toxicity of the cis-complexes 4 and 5 on human bladder cancer cell lines (5637-CDDP, cisplatin-resistant cell line) (b) comparison of cytotoxicities of the cis- and rarcs-isomers 4 and 6 in the dark and upon irradiation cisplatin is included for comparison. Data from Ref. (30).

Although the second generation of platinum drugs is less toxic than cisplatin, many appear to be cross-resistant with cisplatin. Requirements which are influencing the search for new generations of active complexes include (1) lower toxicity to normal cells than cisplatin, (2) activity against tumors with acquired cisplatin resistance, (3) activity against a wider spectrum of types of cancer, and (4) oral activity. 

Ma J, Maliepaard M, Kolker HJ, Verweij J, Schellens JHM (1998a) Abrogated energy-dependent uptake of cisplatin in a cisplatin-resistant subline of the human ovarian cancer cell line IGROV-1. Cancer Chemother Pharmacol 41 186-192... 

Scaglione-Sewell B, Abraham C, Bissonnette M, Skarosi SF, Hart J, Davidson NO, Wali RK, Davis BH, Sitrin M, Brasitus TA (1998) Decreased FKC alpha expression increases cellular proliferation, decreases differentiation, and enhances the transformed phenotype of CaCo-2 cells. Cancer Res 58 1074-1081 Scala S, Dickstein B, Regis J, Szallasi Z, Blumberg PM, Bates SE (1995) Bryostatin 1 affects P-glycoprotein phosphorylation but not function in multidrug-resistant human breast cancer cells. Clinical Cancer Res 1 15851-1587 Scanlon, KJ, Kashani-Sabet M, Tone T, Funato T (1991) Cisplatin resistance in human acancers. Pharmac Ther 52 385-406... 

Fujii R, Mutoh M, Sumizawa T, Chen Z, Yoshimura A, Akiyama S. Adenosine triphosphate-depen-dent transport of leukotriene C4 by membrane vesicles prepared from cisplatin-resistant human epidermoid carcinoma tumor cells. J Natl Cancer Inst 1994 86 1781-1784. 

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