Immune-dependent antineoplastic effects of cisplatin plus pyridoxine in non-small-cell lung cancer

Abstract

cis-Diamminedichloroplatinum(II) (CDDP), which is mostly referred to as cisplatin, is a widely used antineoplastic. The efficacy of cisplatin can be improved by combining it with the vitamin B6 precursor pyridoxine. Here, we evaluated the putative synergistic interaction of CDDP with pyridoxine in the treatment of an orthotopic mouse model of non-small-cell lung cancer (NSCLC). CDDP and pyridoxine exhibited hyperadditive therapeutic effects. However, this synergy was only observed in the context of an intact immune system and disappeared when the otherwise successful drug combination was applied to the same NSCLC cancer implanted in the lungs of athymic mice (which lack T lymphocytes). Immunocompetent mice that had been cured from NSCLC by the combined regimen of CDDP plus pyridoxine became resistant against subcutaneous rechallenge with the same (but not with an unrelated) cancer cell line. In vitro, CDDP and pyridoxine did not only cause synergistic killing of NSCLC cells but also elicited signs of immunogenic cell death including an endoplasmic reticulum stress response and exposure of calreticulin at the surface of the NSCLC cells. NSCLC cells treated with CDDP plus pyridoxine in vitro elicited a protective anticancer immune response upon their injection into immunocompetent mice. Altogether, these results suggest that the combined regimen of cisplatin plus pyridoxine mediates immune-dependent antineoplastic effects against NSCLC.

Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy

“…9 Driven by these considerations, we investigated the potential role of necroptosis in ICD. We found that, in contrast to CT26 and MCA205 cells, which lack the expression of RIP3, other murine cancer cell lines that can undergo ICD, such as the TC-1 lung carcinoma, 33 as well as the EL4 thymoma, 9 express such molecules. To our surprise, necroptotic cancer cells exhibit all biochemical hallmarks of ICD (CRT exposure, ATP and HMGB1 release) and are able to induce a protective anticancer immune response.…”

Anticancer metal drugs and immunogenic cell death

“…D'Orazi and collaborators, for instance, demonstrated that the administration of zinc(II) chloride, which was already studied by the same group for its ability to reactivate p53 in chemoresistant glioblastoma cells [89], in combination with cisplatin to cancer cells (co-cultured with immature DC) triggered ICD [90]. ER stress and CRT exposure can be also promoted by i) thapsigargin known to inhibit the sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA), ii) the UPR inducer tunicamycin and iii) pyridoxine, a precursor of vitamin B6, to support the anticancer effect of cisplatin [60,91]. Also treatment of murine fibrosarcoma cells with the cardiac glycosides digoxin and digitoxin in combination with cisplatin was able to fully immunize mice against a re-challenge with the identical tumor cells and the combination also showed synergistic activity against established tumors in an immunoproficient background only [43].…”

Cisplatin-Induced Antitumor Immunomodulation: A Review of Preclinical and Clinical Evidence

“…HNSCC cells exposed to the combination sublethal CDDP/5-FU were also more susceptible to antigen-specific, MHC-restricted cytotoxic T-cell killing (9). A recent study examining the use of CDDP in combination with the chemosensitizer vitamin B6 precursor, pyridoxine, demonstrated that the synergistic cytotoxicity observed in vitro against non-small cell lung cancer (NSCLC) can translate into improved antitumor efficacy in vivo (29). When given to immunocompetent mice bearing NSCLC tumors, the CDDP/pyridoxine regimen resulted in a 45% cure rate; when given to athymic tumor-bearing mice, this combination CDDP treatment failed to avoid tumor growth and to prolong overall survival, thereby implying that the observed therapeutic effects relied on the presence of thymic-derived T lymphocytes (29).…”