Abstract
Cis-diamminedichloroplatinum(II) (cisplatin, cDDP) is an effective chemotherapeutic agent that induces DNA double strand breaks (DSBs), primarily in replicating cells. Generally, such DSBs can be repaired by the classical or backup non-homologous end joining (c-NHEJ/b-NHEJ) or homologous recombination (HR). Therefore, inhibiting these pathways in cancer cells should enhance the efficiency of cDDP treatments. Indeed, inhibition of HR by hyperthermia (HT) sensitizes cancer cells to cDDP and in the Netherlands this combination is a standard treatment option for recurrent cervical cancer after previous radiotherapy. Additionally, cDDP has been demonstrated to disrupt c-NHEJ, which likely further increases the treatment efficacy. However, if one of these pathways is blocked, DSB repair functions can be sustained by the Poly-(ADP-ribose)-polymerase1 (PARP1)-dependent b-NHEJ. Therefore, disabling b-NHEJ should, in principle, further inhibit the repair of cDDP-induced DNA lesions and enhance the toxicity of thermochemotherapy. To explore this hypothesis, we treated a panel of cancer cell lines with HT, cDDP and a PARP1-i and measured various end-point relevant in cancer treatment. Our results demonstrate that PARP1-i does not considerably increase the efficacy of HT combined with standard, commonly used cDDP concentrations. However, in the presence of a PARP1-i, ten-fold lower concentration of cDDP can be used to induce similar cytotoxic effects. PARP1 inhibition may thus permit a substantial lowering of cDDP concentrations without diminishing treatment efficacy, potentially reducing systemic side effects.
Highlights
Cisplatin (cis-diamminedichloroplatinum(II), cDDP), is one of the most potent and widely used chemotherapeutic agents. cDDP has been successfully applied in treating many different tumor types, including head and neck, lung, testis, ovarian, cervix and breast [1, 2]. cDDP induces formation of intra- and interstrand crosslinks, which may induce DNA single and double strand breaks (SSBs and DSBs) in replicating cells [3, 4]
Mild hyperthermia (HT), 1 h at 41–42.5°C, can disrupt this pathway temporarily by inducing degradation of BRCA2 and preventing the recruitment of RAD51 to DSBs [6]. classical non-homologous end joining (c-NHEJ) is active in all cell cycle phases, rejoins the break ends without the requirement for homologous template and is considered to be more error prone [7,8,9]
We measured the effects of HT on homologous recombination (HR) activity by quantifying accumulation of HR factor RAD51 on alphaparticle induced DSBs
Summary
Cisplatin (cis-diamminedichloroplatinum(II), cDDP), is one of the most potent and widely used chemotherapeutic agents. cDDP has been successfully applied in treating many different tumor types, including head and neck, lung, testis, ovarian, cervix and breast [1, 2]. cDDP induces formation of intra- and interstrand crosslinks, which may induce DNA single and double strand breaks (SSBs and DSBs) in replicating cells [3, 4]. DSBs are repaired by mainly two major pathways: the classical non-homologous end joining (c-NHEJ) and the homologous recombination (HR). HR is mainly active in S- and G2-phase, ensures accurate repair by using the undamaged sister chromatid www.impactjournals.com/oncotarget as a template and involves, among others, BRCA2 and RAD51 [5]. Mild hyperthermia (HT), 1 h at 41–42.5°C, can disrupt this pathway temporarily by inducing degradation of BRCA2 and preventing the recruitment of RAD51 to DSBs [6]. C-NHEJ is active in all cell cycle phases, rejoins the break ends without the requirement for homologous template and is considered to be more error prone [7,8,9]. Besides inducing DNA breaks, cDDP has been shown to disrupt c-NHEJ [10,11,12,13]
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