Anticancer Activity of Methyl-Substituted Oxaliplatin Analogs

Abstract

Oxaliplatin is successfully used in systemic cancer therapy. However, resistance development and severe adverse effects are limiting factors for curative cancer treatment with oxaliplatin. The purpose of this study was to comparatively investigate in vitro and in vivo anticancer properties as well as the adverse effects of two methyl-substituted enantiomerically pure oxaliplatin analogs [[(1R,2R,4R)-4-methyl-1,2-cyclohexanediamine] oxalatoplatinum(II) (KP1537), and [(1R,2R,4S)-4-methyl-1,2-cyclohexanediamine]oxalatoplatinum(II) (KP1691)] and to evaluate the impact of stereoisomerism. Although the novel oxaliplatin analogs demonstrated in multiple aspects activities comparable with those of the parental compound, several key differences were discovered. The analogs were characterized by reduced vulnerability to resistance mechanisms such as p53 mutations, reduced dependence on immunogenic cell death induction, and distinctly attenuated adverse effects including weight loss and cold hyperalgesia. Stereoisomerism of the substituted methyl group had a complex and in some aspects even contradictory impact on drug accumulation and anticancer activity both in vitro and in vivo. To summarize, methyl-substituted oxaliplatin analogs harbor improved therapeutic characteristics including significantly reduced adverse effects. Hence, they might be promising metal-based anticancer drug candidates for further (pre)clinical evaluation.

Anticancer metal drugs and immunogenic cell death

“…Also in our hands, oxaliplatin was inactive in the immuno-deficient (SCID) background but fully active in the wild-type mice. In contrast, the novel oxaliplatin derivatives demonstrated significant activity also in the immunosuppressed host, although the anticancer effects were distinctly weaker as compared to the immunocompetent animals [64]. These data indicate that only minor differences in the chemical structure might have a decisive impact on the induction of immune-related effects by anticancer metal drugs.…”

“…In this context, CD47-blocking antibodies can also be considered potential factors to be used in ICD combinatorial strategies. Taking into account the broad involvement of ROS-mediated processes and ER stress in the mode-of-action of multiple experimental anticancer metal drugs mentioned above [64,78,79,[81][82][83][84][85][86][87], some of these compounds might also act as ICD adjuvants.…”

Autophagy impacts on oxaliplatin-induced hepatocarcinoma apoptosis via the IL-17/IL-17R-JAK2/STAT3 signaling pathway

“…Furthermore, autophagy during chemotherapy has been shown to induce chemoresistance (28), while sensitivity to chemotherapy was increased when autophagy was inhibited (29,30). It is well known that decreased susceptibility to apoptosis during chemotherapy is the main mechanism of chemoresistance (31,32). LC3 is a specific marker of autophagosomes in mammalian cells, and the conversion of the soluble form of LC3 (LC3-I) to the autophagosome-associated form (LC3-II) is a characteristic of autophagy (33)(34)(35).…”

Rákellenes gallium- és platinafém komplexek oldatkémiája, kölcsönhatásuk vérszérum-fehérjékkel és DNS-sel

“…B.K. Keppler és kutatócsoportja olyan oxaliplatin származékokat állított elő, ahol a diamino-ciklohexán gyűrű 4-es pozíciójában egy metilcsoport található [30]. Ez egy további kiralitáscentrumot eredményez a molekulán.…”

“…Megfigyelték, hogy a 4R konfigurációjú KP1537 ([Pt(II)((1R,2R,4R)-4-metil-1,2-ciklohexándiamin)oxalát]) komplex in vivo kísérletekben nagyobb aktivitást mutat, mint a 4S konfigurációjú KP1691, és nem jelentkezik az oxaliplatin kezeléskor gyakran kialakuló hideg túlérzékenység. Az egyes komplexek sejtekbe történő felvételében is különbség mutatkozott, ennek pontos, molekuláris oka azonban egyelőre nem ismert [30]. …”