Small molecules in combination with conventional chemotherapeutic drugs: Light at the end of the tunnel?

Abstract

Recent studies have shown BI2536 and bortezomib to be effective in squamous cell carcinoma of the head and neck (SCCHN) cell lines. In this systemic in vitro study, we examined the antitumor effect of the small molecules BI2536 and bortezomib in combination with cisplatin or docetaxel in nine squamous cell carcinoma cell lines, most of head and neck origin. Dose escalation studies were performed with these cell lines using bortezomib, BI2536, cisplatin and docetaxel in cell line-specific concentrations. Growth inhibitory and proapoptotic effects were measured quantitatively using cytohistology and the Human Apoptosis Array kit. The combination of bortezomib and BI2536 with cisplatin or docetaxel showed a significantly higher antiproliferative and apoptotic activity in all SCCHN cell lines investigated compared with single agent cisplatin or docetaxel alone (P≤0.021). Combination of conventional chemotherapeutic drugs, such as cisplatin and docetaxel, with small molecules in the clinical setting may enhance the antitumor activity of these agents and may lead to less toxic side-effects and a more effective cancer therapy.

Figure 1

Growth inhibitory effect of cisplatin or docetaxel alone and in combination with bortezomib/BI2536 at a fixed cell line-specific concentration as shown in Table I after 72 h treatment in the PE/CA-PJ 49 tumor cell line. The untreated tumor cells (light grey column) served as a control and were incubated according to the supplier’s instructions with antibiotics at 37°C in the cell type-specific Quantum 263 medium with L-glutamine. The absolute tumor cell numbers in the treated and control cell lines were determined in a Rosenthal chamber at 72 h after treatment or incubation with Quantum 263, respectively. Mean values of three independent experiments with standard deviation are shown. Significant differences between single agent and combination treatment and untreated controls are indicated by asterisks. Combination treatment of bortezomib/BI2536+cisplatin or +doectaxel significantly inhibited cell proliferation compared with mono drug therapy with cisplatin or docetaxel alone (P≤0.021).

Figure 2

Growth inhibitory effect of cisplatin or docetaxel alone and in combination with bortezomib/BI2536 at a fixed cell line-specific concentration as shown in Table I after 72 h treatment in the SCC-14C tumor cell line. The untreated tumor cells (light grey column) served as a control and were incubated according to the supplier’s instructions with antibiotics at 37°C in the cell type-specific Quantum 263 medium with L-glutamine. The absolute tumor cell numbers in the treated and control cell lines were determined in a Rosenthal chamber at 72 h after treatment or incubation with Quantum 263, respectively. Mean values of three independent experiments with standard deviation are shown. Significant differences between single agent and combination treatment and untreated controls are indicated by asterisks. Combination treatment of bortezomib/BI2536+cisplatin or +doectaxel significantly inhibited cell proliferation compared with mono drug therapy with cisplatin or docetaxel alone (P≤0.021).