Molecular markers of DNA damage and repair in cervical cancer patients treated with cisplatin neoadjuvant chemotherapy: an exploratory study

CIOCCA, DANIEL R.; RÖHRICH, HANNA; CASTRO, GISELA N.; GUERRERO-GIMENEZ, MARTIN E.; PERINETTI, CLAUDIA; REAL, NILDA E.; CAYADO-GUTIÉRREZ, NIUBYS; DARÍO CUELLO-CARRIÓN, F.; CIOCCA, DANIEL R.; RÖHRICH, HANNA; CASTRO, GISELA N.; GUERRERO-GIMENEZ, MARTIN E.; PERINETTI, CLAUDIA; REAL, NILDA E.; CAYADO-GUTIÉRREZ, NIUBYS; DARÍO CUELLO-CARRIÓN, F.

CELL STRESS & CHAPERONES.

SPRINGER

Lugar: Berlin; Año: 2017 vol. 22 p. 811 - 822

1355-8145

Neoadjuvant (or induction) chemotherapy can beused for cervical cancer patients with locally advanced disease;this treatment is followed by radical surgery and/or radiationtherapy. Cisplatin is considered to be the most activeplatinum agent drug for this cancer, with a response rate of20%. In order to understand how the cisplatin treatment affectsthe stress response, in this work, we performed an exploratorystudy to analyze a number of stress proteins beforeand after cisplatin neoadjuvant chemotherapy. The study involved14 patients; the pre- and post-chemotherapy pairedbiopsies were examined by hematoxylin and eosin stainingand by immunohistochemistry. The proteins evaluated werep53, P16/INK4A, MSH2, nuclear protein transcriptional regulator1 (NUPR1), and HSPB1 (total: HSPB1/t and phosphorylated:HSPB1/p). These proteins were selected because thereis previous evidence of their relationship with drug resistance.The formation of platinum-DNA adducts was also studied.There was a great variation in the expression levels of thementioned proteins in the pre-chemotherapy biopsies. Afterchemotherapy, p53 was not significantly affected by cisplatin,as well as P16/INK4A and MSH2 while nuclear NUPR1content tended to decrease (p = 0.056). CytoplasmicHSPB1/t expression levels decreased significantly followingcisplatin therapy while nuclear HSPB1/t and HSPB1/p tendedto increase. Since the most significant changes following chemotherapyappeared in the HSPB1 expression levels, thechanges were confirmed by Western blot. The platinum-DNA adducts were observed in HeLa cell in apoptosis; however,in the tumor samples, the platinum-DNA adducts wereobserved in morphologically healthy tumor cells; these cellsdisplayed nuclear HSPB1/p. Further mechanistic studiesshould be performed to reveal how HSPB1/p is related withdrug resistance. When the correlations of the markers with theresponse to neoadjuvant chemotherapy were examined, onlyhigh pre-chemotherapy levels of cytoplasmic HSPB1/p correlatedwith a poor clinical and pathological response to neoadjuvantcisplatin chemotherapy (p = 0.056) suggesting that thismarker could be useful opening its study in a larger number ofcases.